ord" />ord" />ord" /> ord" /> TNF-? modulates genome-wide redistribution of ?Np63?/TAp73 and NF-?B c-REL interactive binding on TP53 and AP-1 motifs to promote an oncord" /><meta name="ncbi_type" content="fulltext" /><metord" /><meta name="ncbi_type" content="fullord" /><meta name="ncbi_type" content="fulltord" /><meta name="ncbi_type" content="fulltext" ord" /><meta name="ncbi_type" content="fulltext" /><meta naord" /><meta name="ncbi_type" content="fulltext" /><meta name="ncbi_objectid" content="" /><meord" /><meta name="ncbi_type" content="fulltext"ord" /><meta name="ncbi_type" content="fulltext" /ome-wide redistribution of ?Np63?/TAp73 and NF-?B c-REL interactive binding on TP53 and AP-1 motifs to promote an oncogenic gene program in squamous cancer" />ome-wide redistribution of ?Np63?/ome-wide redistribution of ?Np63?/TAp73 and NF-?B c-ome-wide redistribution of ?Np63?/TAp73 andome-wide redistribution of ?Np63?/TAp73 andome-wide redistribution of ?Np63?/TAp73 and NF-?Bome-wide redistribution of ?Np63?/TAp73 and NF-?B ome-wide redistribution of ?Np63?/TAp73 and NF-?B ome-wide redistribution of ?Np63?/TAp73 and NF-?Bome-wide redistribution of ?Np63?/TAp73 and NF-?Bome-wide redistribution of ?Np63?/TAp73 and NF-?B ome-wide redistribution of ?Np63?/TAp73 and ome-wide redistribution of ?Np63?/TAp73 and NF-?B ome-wide redistribution of ?Np63?/TAp73 andome-wide redistribution of ?Np63?/TAp73 and NF-?B ome-wide redistribution of ?Np63?/TAp73 and NF-?B c-Rome-wide redistribution of ?Np63?/TAp73 and NF-ome-wide redistribution of ?Np63?/TAp73 and NF-?B c-Rome-wide redistribution of ?Np63?/TAp73 and NF-?Bome-wide redistribution of ?Np63?/TAp73 and NF-?ome-wide redistribution of ?Np63?/TAp73 and ome-wide redistribution of ?Np63?/TAp73 and NF-?B come-wide redistribution of ?Np63?/TAp73 and NF-?B c-RELome-wide redistribution of ?Np63?/TAp73 and NF-?B c-Rome-wide redistribution of ?Np63?/TAp73 and NF-?B c-ome-wide redistribution of ?Np63?/TAp73 and NF-?B c-ome-wide redistribution of ?Np63?/TAp73 and NF-ome-wide redistribution of ?Np63?/TAp73 ome-wide redistribution of ?Np63?/TAp73 and NF-?B c-REL ome-wide redistribution of ?Np63?/TAome-wide redistribution of ?Np63?/TAp73 and NF-?B c-REL interactive binding on TP53 and AP-1 motifs to promote an oncogenic gene program in squamous cancer" /><meta name="DC.Type" content="Text" /><meta name="DC.Pome-wide redistribution of ?Np63?/TAp73 aome-wide redistribution of ?Np63?/TAp73 and NF-?B c-REL interactive binding on TP53 and AP-types (PanCancer 12) revealed frequent mutation of TP53, and amplification and expression of related TP63 isoform ?Np63 in squamous cancers. Further, aberrant expression of inflammatory ..." />types (PanCancer 12) revealed frequent mutation of TP53, and amplification and exptypes (PanCancer 12) revealed frequent mutation of TP53, antypes (PanCancer 12) revealed frequent mutation of TP53, and amplification and expression of relatetypes (PanCancer 12) revealed frequent muttypes (PanCancer 12) revealed frequent m<link rel="stylesheet" href="/corehtml/pmc/css/3.8/pmc.min.css" type="text/css"/><link rel="stylesheet" href="/corehtml/pmc/css/3.8/pmc_extras_prnt.min.css" type="text/css" media="print"/><script type="text/javascript" src="/corehtml/pmc/js/common.min.js">ty</script><script type="text/javascript" src="/corehtml/pmc/js/NcbiTagServer.min.js">ty</script>types (PanCancer 12) revealed frequent mutation of TP53, and ampl<script type="text/javascript" src="/corehtml/pmc/ctxp/jquery.citationexporter.js">ty</script><link rel="stylesheet" href="/corehtml/pmc/ctxp/citationexporter.css" type="text/css"/><script type="text/javascript" src="/core/mathjax/2.6.1/MathJax.js?config=/corehtml/pmc/js/mathjax-config-classic.3.4.js"></script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"></script><script type="text/javascript">types (PanCancer 12) </script>types (PanCancer 12) revealed frequent mutation of TP53, and amplification and expression of related TP63 isoform ?Np63 in squamous cancers. Further, typestypes (PanCancer 12) revealed frequent mutatitypestypes (PanCancer 12) revealed frequent mutation of TP53, and amplification and expression of related TP63 isoform ?Np63 in squamous cancers. 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Author manuscript; a<a href="/pubmed/?term=Si%20H%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">OncogeOncogOncogenOncogeOncogeOncogen<a href="/pubmed/?term=Lu%20H%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">OncogeOncogOncogenOncogeOncogeOncogen<a href="/pubmed/?term=Yang%20X%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">Oncogene</spOncogOncogeOncogen<a href="/pubmed/?term=Mattox%20A%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=27132513"uid=2uid=27uid=271<a href="/pubmed/?term=Jang%20M%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=27132513"uid=2uid=27uid=271<a href="/pubmed/?term=Bian%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=27132513uid=2uid=27uid=271<a href="/pubmed/?term=Sano%20E%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=27132513uid=2uid=27uid=271<a href="/pubmed/?term=Viadiu%20H%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=27132513"uid=2uid=27uid=271<a href="/pubmed/?term=Yan%20B%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=271uid=2uid=27uid=271<a href="/pubmed/?term=Yau%20C%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=27132513"uid=2uid=27uid=271<a href="/pubmed/?term=Ng%20S%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=27uid=2uid=27uid=271<a href="/pubmed/?term=Lee%20SK%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=27132513"uid=2uid=27uid=271<a href="/pubmed/?term=Romano%20RA%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=27132513">Auuid=2uid=27uid=271<a href="/pubmed/?term=Davis%20S%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=271325uid=2uid=27uid=271<a href="/pubmed/?term=Walker%20RL%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=27132513">Auuid=2uid=27uid=271<a href="/pubmed/?term=Xiao%20W%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=27132513uid=2uid=271uid=271<a href="/pubmed/?term=Sun%20H%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=2713251uid=2uid=271uid=271<a href="/pubmed/?term=Wei%20L%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=271uid=2uid=2713uid=27uid=271uid=271<a href="/pubmed/?term=Sinha%20S%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=27132513">uid=2uid=27uid=271<a href="/pubmed/?term=Benz%20CC%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=27132513">Austuid=2uid=27uid=271<a href="/pubmed/?term=Stuart%20JM%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">uid=27132513">Au</a>,a>,<sua>,<sup<a href="/pubmed/?term=Meltzer%20PS%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">a>,<sup>7</sup>a>,<sa>,<sua>,<sup<a href="/pubmed/?term=Van%20Waes%20C%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">a>,<sup>7</sup>a>,<sa>,<supa>,<sua>,<sua>,<sup>7</s<a href="/pubmed/?term=Chen%20Z%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">a>,<sup>7<a>,<a>,<supa>,<sua>,<sua>,<sua>,<sua>,<sua>,<sup>7</sup> <a href="/pubmed/?term=Ma>,<sup>7</sup> <a href="/pubmed/?term=Meltzer%20PS%5BAuthor%5D&cauthor=true&cauthor_uid=271325a>,<sup>7</sup> <a href="/pubmea>,<sua>,<sup>7</sup> <a href="/pubmed/?term=Meltzer%20PS%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">Paul S. Meltzer</a>,<sup>9</sup> <a href="/puba>,<sua>,<sup>7</sup> <a href="/pubmea>,<sua>,<sup>7</sup> <a href="/pubmed/?term=Meltzer%20PS%5BAuthor%5D&caua>,<sua>,<sup>7</sup> <a href="/pubmea>,<sua>,<sup>7</sup> <a href="/pubmed/?term=Meltzer%20PS%5BAuthor%5D&cauthor=true&cauthor_uid=a>,<sua>,<sup>7</sup> <a href="/pubmea>,<sua>,<sup>7</sup> <a href="/pubmed/?term=Meltzer%20PS%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">Paul S. Meltzer</a>,<sup>9</sup> <a href="/pubmed/?term=Van%20Waes%20C%5Ba>,<sua>,<sup>7</sup> <a href="/pubmea>,<sua>,<sup>7</sup> <a href="/pubmed/?term=Meltzer%20PS%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">Paul S. Meltzer</a>,<sup>9</sup> <a href="/pubmed/?term=Vaa>,<sua>,<sup>7</sup> <a href="/pubmea>,<sua>,<sup>7</sup> <a href="/pubmed/?term=Meltzer%20PS%5Ba>,<sua>,<sup>7</sup> <a href="/pubmea>,<sua>,<sup>7</sup> <a href="/pubmed/?term=Meltzer%20PS%5BAuthor%5D&cauthor=true&cauthor_uid=27132513">Paul Sifornia, Santa Cruz, Santa Cruz, CAiforniifornia, Santa Cruz, Santa Cruziforniifornia, Santa Cruz, Santa Cruz, CA</div><div class="fm-affl" lang="en"><sup>8</sup>Department of Biochemistry, State University of New York at Buffalo, Ceniforniifornia, Santa Cruz, Santa Cruziforniifornia, Santa Cruz, Santa Cruz, CA</div><div class="fm-affl" lang="en"><sup>8</iforniifornia, Santa Cruz, Santa Cruziforniaifornia, Santa Cruz, Santa Cruz, CA</div><div class="fm-affl" lang="en"><sup>8</sup>Department of Biochemistry, State University of New York at Buffaliforniifornia, Santa Cruz, Santa Cruziforniaifornia, Santa Cruz, Santa Cruz, CA</div><div class="fm-affl" lang="en"><sup>8</sup>Department of Biochemistry, State University of Newiforniifornia, Santa Cruz, Santa Cruziforniaifornia, Santa Cruz, Santa Cruz, CA</div><div class="fm-affl" lang="en"><sup>8</sup>Depaiforniifornia, Santa Cruz, Santa Cruziforniaifornia, Santa Cruz, Santa Cruz, CA</div><div class="fm-affl" lang="en"><sup>8</sup>Department of Biochemistry, Staiforniifornia, Santaiforniifornia, Santa Cruz, Santaiforniifornia, Santaiforniifornia, Santa Cruz, Santa Cruz, CA</div><div class="fm-affl" lang="en"><sup>8</sup>Department of Biochemistry, <a href="mailto:dev@null" data-email="vog.hin.dcdin@znehc" class="oemail">ifornia, Santa Cruzifornia, Santa Cruz, Santa Cruz, CA</div><div class="fm-affl" lang="en"><sup>8</sup>Department of Biochemistry, State University of New York <a href="mailto:dev@null" data-email="vog.hin.dcdin@cseawnav" class="oemail">ifornia, Santa Cruz, Sifornia, Santa Cruz, Santa Cruz, CA</div><diviforniiforniifornia, Santa Cruz, S<a href="#" class="pmctoggle" rid="idm140671044703776_ai">ifornia, Santa Cruziforniaiforniaiforn<a href="#" class="pmctoggle" rid="idm140671044703776_cpl">ifornia, Santa Cruz, Santa Cruz, Ciforniaiforniaiforiforniifornia, Santa Cruz, Santa Cruz, CA</div><div classiforniifornia, Santa Cruz, fo fm-panel hide half_rhythm" id="idm140671044703776_cpl" style="display:none">fo fm-panel hide half_rhythm" id="idm1<a href="/pmc/about/copyright/">fo fm-panel hidefo fm-pane<a href="/pmc/about/disclaimer/">fo fm-panefo ffo fm-fo fm-panel hide half_rhythm" id="idm1fo fm-panel hide half_rhythm" id="idm140671044703776_cpl" style="display:none"><div class="fm-copyright half_rhythm"><a href="/pmc/about/copyright/">Copyright notice</a> and <a href="/pmc/about/di<a href="http://www.nature.com/authors/editorial_policies/license.html#terms">fo fm-panel hide half_rhythm" id="idm140671044703776_cpl" style="difo ffo fm-fo fm-fo fm-fo fm-fo fm-panel hide half_rhythm" id="idm140671044703776_fo fm-panel hide hafo fm-panel hide half_rhythm" id="idm140671044703776_cpl" style="display:no<a href="/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=27132513" target="pmc_ext" ref="reftype=publisher&article-id=5093089&issue-id=278503&journal-id=319&FROM=Article%7CFront%20Matter&TO=Content%20Provider%7CArticle%7CRestricted%20Access&rendering-type=normal">fo fm-pafo ffo fm-fo fm-fo fm-fo fm-fo fm-panel hide fo fm-fo fm-panel hide half_rhythm" id="idm140671044703776_cpl" style="dfo fm-panel hide half_rhythm" id="idm140671044703776_cpl" style="display:none"><dfo fmfo fm-panel hide hafo fmfo fm-panel hide half_rhythm" id="idm140671044703776_cpl" style="display:none"><div class="fm-copyright half_rhythm"><a href="/pmc/about/copyright/">Copyright notice</a> and <a href="/pmc/about/disclaimer/">Disclaimer</a></div><div class="fm-copyright half_rhythm"><div class="license">Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:<a href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</a></div></div></div></div><div id="pmclinksbox" class="links-box whole_rhythm"><div class="small"><din of cREL with ΔNp63α/TAp73 complexes and signatures genome-wide in the HNSCC model UM-SCC46 using chromatin immunoprecipitation sequencing (ChIP-seq). TNF-α enhanced genome-wide co-occupancy of cREL with ΔNp63α on TP53/p63 sites, while unexpectedly promoting redistribution of TAp73 from TP53 to Activator Protein-1 (AP-1) sites. cREL, ΔNp63α, and TAp73 binding and oligomerization on NF-κB, TP53 or AP-1 specific sequences were independently validated by ChIP-qPCR, oligonucleotide-binding assays, and analytical ultracentrifugation. Function of the binding activity was confirmed using TP53, AP-1, and NF-κB specific response elements, or n of cREL with &#n of cREL wn of cREn of cREL with ΔNp63α/TAp73 complexes and signatures genome-wide in the HNSCC model UM-SCC46 using chromatin immunoprecipitation sequencing (ChIP-seq). TNF-α enhanced genome-wide co-occupancy of cREL with ΔNp63α on TP53/p63 sites, while unexpectedly promoting redistribution of TAp73 from TP53 to Activator Protein-1 (AP-1) sites. cREL, ΔNp63α, and TAp73 binding and oligomerization on NF-κB, TP53 or AP-1 specific sequences were independently validated by ChIP-qPCR, oligonucleotide-binding assays, and analytical ultracentrifugation. Function of the binding activity was confirmed using TP53, AP-1, and NF-κB specific response elements, or <em>p21, SERPINE1</em>, and <em>IL-6</em> promoter luciferase reporter activities. Concurrently, TNF-α regulated a broad gene network with co-binding activities for cREL, ΔNp63α, and TAp73 observed upon array profiling and RT-PCR. Overlapping tn ofn of cn of cREL with &#n of cREL with ΔNp63αn of cRELn of cREL withwd-text">TNF-alpha, cRel, ΔNp63α, TAp73, ChIP-seqwd-textwd-texwd-texwd-text">TNF-alpha, cRel, �wd-text">TNF-alpha, cRel, ΔNp63α, TAp73, Chwd-tewd-text">TNF-alpha, cRel, ΔNp63α, TAp73, ChIP-seq</span></div></div><div id="S1" class="tsec sec"><h2 class="head no_bottom_margin" id="S1title">Introduction</h2><p id="P3" class="p p-first">The Cancer Genome Atlas (TCGA) project aims to provide a comprehensive catalog of the key genomic changes in major cancer types, in order to foster effective diagnosis, treatment and prevention. The recently published TCGA HNSCC (head and neck squamous cell carcinoma) project, including 279 patient tissues, revealed that more than 84% of HPV negative HNSCC harbor genetic alterations in tumor suppressor TP53, concurrent wit<a href="#R1" rid="R1" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401336">wwd-text">TNF-alpha, cRel, ΔNp63α, TAp73, ChIP-seq</span></div></div><div id="S1" class="tsec sec"><h2 class="head no_bottom_margin" id="S1title">Introduction</h2><a href="#R2" rid="R2" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401335">wwd-text">TNF-alpha, cRel, ΔNp63α, TAp73, ChIP-seq</span></div></div><div id="S1" class="tsec sec"><h2 class="head no_bottom_margin" id="S1title">Introduction</h2><p id="P3" class="p p-first">The Ca<a href="#R2" rid="R2" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401311">wwd-text">TNF-alpha, cRel, ΔNp63α, TAp73, ChIP-seq</span></div></div><div id="S1" class="tsec sec"><h2 class="head no_bottom_margin" id="S1title">Introduction</h2><p id="P3" class="p p-first">The Cancer Genome Atlas (TCGA) project aims to provide a comprehensive catalog of the key genomic changes in major cancer types, in order to foster effective diagnosis, treatment and prevention. The recently published TCGA HNSCC (head and neck squamous cell carcinoma) project, including 279 patient tissues, revealed that more than 84% of HPV negative HNSCC harbor to what extent do TP63/TP73 and NF-κB/REL family transcription factors interact to regulate global gene programs in squamous cancers? to to what extent do TP63/TP73 and NF-κB/REL family transcription factors interact to regulate global gene programs in squamous cancers?</p><p id="P4">The TP53 family comprises TP53, TP63, and TP73 and their isoforms. TP53 is the most frequently mutated tumor suppressor gene in cancer, especially in squamous cancers, and is described as the “guardian of the genome.” Mutation or inactivation of T<a href="#R3" rid="R3" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401365"> to what extent do TP63/TP73 and NF-κB/REL family transcription factors interact to regulate global gene programs in squamous cancers?</p><p id="P<a href="#R4" rid="R4" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401341"> to wh<a href="#R5" rid="R5" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401323"> to what extent do TP63/TP73 and NF-κB/REL family transcription factors interact to regulate global gene programs in squamous cancers?</p><p id="P4">The TP53 family comprises TP53, TP63, and TP73 and their isoforms. TP53 is the most frequently mutated tumor suppressor gene in cancer, especially in squamous cancers, and is described as the “guardian of the genome.” Mutation or inactivation of TP53 promotes ge<a href="#R4" rid="R4" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401348"> to wh<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401316"> to w<a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401296"> to what extent do TP63/TP73 and NF-κB/REL family transcription factors interact to regulate global gene programs in squamous cancers?</p><p id="P4">The TP53 family comprises TP53, TP63, and TP73 and their isoforms. TP53 is the most frequently mutated tumor s<a href="#R9" rid="R9" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401284">lltip" <a href="#R10" rid="R10" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401343">ltltip" id="__tag_569401284">9</a>, <a href="#R10" rid="R10" class=" bibr popnode tag_hotlink tag_tooltiigenesis and linked to inflammation in cancer are undefined.igenigenesis and linked to inflammation in cancer are undefined.</p><p id="P5">We recently revealed that inflammatory cytokine TNF-α stimulates binding of NF-κB subunit cREL with ΔNp63 to form a protein complex and displacement of TAp73 DNA binding,igenesis and linked toigenesis anigenesisigenesi<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401342">iigenesis and linked to inflammation in cancer are undefined.</p><p id="P5">We recently revealed that inflammatory cytokine TNF-α stimu<a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401322">iigenesis and linked to inflammation in cancer are undefined.</p><p id="P5">We recently revealed that inflammatory cytokine TNF-α s<a href="#R11" rid="R11" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401276">igigenesis and linked to inflammation in cancer are unde<a href="#R12" rid="R12" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401266">igigenesis and linked to inflammation in cancer are undefined.</p><p id="P5">We recently revealed that inflammatory cytokine TNF-α stimulates binding of NF-κB subunit cREL with ΔNp63 to form a protein complex and displacement of TAp73 DNA binding, leading to the repression of growth arrest and apoptotic genes <em>CDKN1A (p21), NOXA</em>, and <em>PUMA</em> (<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401342">6</a>). Complexes between cREL, RELA and ΔNp63 were also implicated in reciprocal activation of several NF-κB regulated genes (<a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooigenigenesis and linked to inflammation in cancer are undefined.</p><p id="P5">We recently revealed that inflammatory cytokine TNF-α stimulates binding of NF-κB subunit cREL with ΔNp63 to form a protein complex and displacement of TAp73 DNA binding, leading to t003b1; and TAp73 complexes. Furthermore, bioinformatic analysis of 003b1; and 003b1; and TAp73 complexes. Furthermore, bioinformatic analysis of <em>in vivo</em> data from TCGA, immunohistochemistry and tissue array of HNSCC, and a ΔNp63α transgenic mouse model supports their contribution in the regulation of the cancer gene program. These findings present a new paradigm for how TNF-α and these TFs orchestrate gene programs implicated in cancer-related inflammation, survival, and migration, and help explain the mechanisms underpinning the dysreg003b003b1;003b1; and TAp73 complexes. Fu003b1; and TAp73 complexes. Furthermore, bioinformatic003b1003b1; and TAp73 complexes. Further003b1; and TAp73 complexes. Furthermore, bioinformatic analysis of <em>in vivo</em> data from TCGA, immunohistochemistry and tissue array of HNSCC, aart sites genome-wideart sart sites genome-wide</h3><p id="P7" class="p p-first-last">To investigate cREL, p63α and TAp73 binding activity genome-wide, ChIP-seq was performed using UM-SCC46 cells, previously shown to exhibit higher expression of mtTP53, TP63 and TP73 proteins, and TNF-α modulation of their interactions in target gene regulation representat<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401287">aart sites genome-wide</h3><p id="P7" class="p p-first-last">To investigate cREL, p63α and TAp73 binding activity genome-wide, ChIP-seq was pe<a href="/pmc/articles/PMC5093089/figure/F1/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1">art sites genomart sitart sites genome-wide</h3><p id="P7" class="p p-first-last">To investigate cREL, p63α and TAp73 bi<a href="#SD1" rid="SD1" class=" supplementary-material">art sites art sites genome-wide</h3><p id="P7" class="p p-first-last">To investigate cREL, p63α and TAp73 binding activity genome-wide, ChIP-seq was performed using UM-SCC<a href="/pmc/articles/PMC5093089/figure/F1/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1">art sites genomart sitart si<a href="#SD12" rid="SD12" class=" supplementary-material">art siteart sites genome-wide</h3><p id="P7" class="p p-first-last">To in<a href="#SD1" rid="SD1" class=" supplementary-material">art sites art si<a href="#SD3" rid="SD3" class=" supplementary-material">arart sites genome-wide</h3><p id="P7" class="p p-first-last">To investigate cREL, p63α and TAp73 binding activity genome-wide, ChIP-seq was performed using UM-SCC46 cells, previously shown to exhibit higher expression of<a href="/pmc/articles/PMC5093089/figure/F1/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1">art sites genomart sitart sites genome-wide</h3><p id="P7" class="p p-first-last">To is were within the promoter (~7-12%) and intragenic regions (35-41%). These peri-genic region peak distributions were significantly enriched compared with the whole genome background distribution, tested using the exact binomial test (<a href="#SD4" rid="SD4" class=" supplementary-material">s were wis were within the promoter (~7-12%) and intragenic regions (35-41%). These peri-genic region pe<a href="/pmc/articles/PMC5093089/figure/F1/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1">s were within ts were s were within the promoter (~7-12%) and intragenic regions (35-41%). These peri-genic region peak distributions were significantly enriched compared with the whole genome background distribution, tested using the exact binom<a href="/pmc/articles/PMC5093089/figure/F1/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1">="figure" class="figur="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1"><span>Figure 1D</span></a>). The intersection sets of three TF binding peaks within 1 kb distance were identified, showing tha<a href="/pmc/articles/PMC5093089/figure/F1/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1">="figure" class="figur="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1"><span>Figure 1D</span></a>). The intersection se<a href="/pmc/articles/PMC5093089/figure/F1/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1">="figure" class="figur="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1"><span>Figure 1D</span></a>). The intersection sets of three TF binding peaks within 1 kb distance were identified, showing th<a href="#SD5" rid="SD5" class=" supplementary-material">="figure"="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1"><span>Figure 1D</span></a>). The intersection sets of three <a href="/pmc/articles/PMC5093089/figure/F1/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1">o-legend-rid="lo-legeno-legend-rid="lgnd_F1"><span>Figure 1F</span></a>). TNF-α increased intersection binding peaks between cREL and p63α, or between p63α and T<a href="/pmc/articles/PMC5093089/figure/F1/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1">o-legend-rid="lo-legeno-legend-rid="lgnd_F1"><span>Figure 1F</span></a>). TNF-α<a href="/pmc/articles/PMC5093089/figure/F1/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1">o-legend-rid="lo-legeno-legend-rid="lgnd_F1"><span>Figure 1F</span></a>). TNF-α<a href="#SD11" rid="SD11" class=" supplementary-material">o-legend-rid="lgnd_F1"><o-legend-rid="lgnd_F1"><span>Figure 1F</span></a>). TNF-α increased intersection binding peaks between cREL and p63α, or betweeo-leo-legend-rid="o-legen mode=article f1--> mode=article f1--><div class="fig iconblock ten_col whole_rhythm clearfix" id="F1" co-le<a class="icnblk_img figpopup" href="/pmc/articles/PMC5093089/figure/F1/" target="figure" rid-figpopup="F1" rid-ob="ob-F1"><img src="/pmc/articles/PMC5093089/bin/nihms-753191-f0001.gif" class="small-thumb" alt="Figure 1" title="Figure 1" src-large="/pmc/articles/PMC5093089/bin/nihms-753191-f0001.jpg" /> mod mode=article f1--><div class="fig icon mode<a class="figpopup" href="/pmc/articles/PMC5093089/figure/F1/" target="figure" rid-figpopup="F1" rid-ob="ob-F1"> mode=ar mod mode= mode=article f1- mode mode= mode=article f1- mode=article f1--><div class="fig iconblock ten_col whole_rhythm clearfix" id="F1" co-legend-rid="lgnd_F1"><a class mode=art mode=a mode= mode= mode= mode= mode=article f1--><div c mode=article f1--><div class="fig iconblock ten_col whole_rhythm clearfix" id="F1" co-legend-rid="lgnd_F1"><a clas mode mode=article f1--><div class="fig iconblock ten_col whole_rhythm clearfix" id="F1" co-legend-rid="lgnd_F1"><a class="icnblk_img figpopup" href="/pmc/articles/PMC5093089/figure/F1/" target="<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2"> mode=article f1- mode=a mode=<a href="#SD6" rid="SD6" class=" supplementary-material"> mode=art mode=article f1--><div class="fig <a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2"> mode=article f mode=a mode=article f1--><div class="fig iconblock ten_col whole_rh<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2"> mode=article f mode=a mode=article f1--><div class="fig iconblock ten_col whole_rhythm clearfix" id="F1" co-l<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2">-legend-rid="lg-legend-legend-rid="lgnd_F2"><span>Figure 2C</span></a>, left) and TNF-α induced TAp73 bindings (D, left) were enriched for AP-1 consensus motifs. A narrow d<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2">-legend-rid="lg-legend-legend-rid="lgnd_F2"><span>Figure 2C</span></a>, left) and TNF-α in<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2">-legend-rid="lg-legend-legend-rid="lgnd_F2"><span>Figure 2C</span></a>, left) and TNF-α induced TAp73 bindings (D, left) were enriched for AP-1 consens<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2">-legend-rid="lg-legend-legend-rid="lgn<a href="#SD6" rid="SD6" class=" supplementary-material">-legend-r-legend-rid="lgnd_F2"><span>Figure 2C</span></a>, left) and TN<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2">-legend-rid="lg-legend-legend-rid="lgnd_F2"><span>Figure 2C</span></a>, left) and TNF-α induced TAp73 bindings (D, left) were enriched for AP-1 consensus motifs. A narrow distributio<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2">-legend-rid="lg-legend-legend-rid="lgnd_F2"><span>Figure 2C</span></a>, left) and TNF-α induced TAp73 bindings (D, left) were enriched for AP-1 consensus motifs. A narr<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2">-legend-rid="lg-legend-legend-rid="-leg-legend-rid="l-legend-rid="lgnd_F2"><spa-legend-rid="lgnd_F2"><span>Figure 2C</span></a>learfix" id="F2" co-legend-rid="lgnd_F2"><a class="icnblk_img figpopup" href="/pmc/articles/PMC5093089/figure/F2/" target="figure" rid-figpopup="F2" rid-ob="ob-F2"><img src="/pmc/articles/PMC5093089/bin/nihms-753191-f0002.gif" class="small-thumb" alt="Figure 2" title="Figure 2" src-large="/pmc/articles/PMC5093089/bin/nihms-753191-f0002.jpg" />learlearfix" id="F2" co-legend-rid="lgnd_F2learf<a class="figpopup" href="/pmc/articles/PMC5093089/figure/F2/" target="figure" rid-figpopup="F2" rid-ob="ob-F2">learfix"learlearfilearfix" id="F2" learflearfilearfix" id="F2" learfix" id="F2" co-legend-rid="lgnd_F2"><a class="icnblk_img figpopup" hlearfix" learfixlearfilearfilearfilearfilearfix" id="F2" co-legenlearfix" id="F2" co-legend-rid="lgnd_F2"><a class="icnblk_img figpopup" href="/pmc/articles/PMC5093089/figure/F2/" targlearflearfix" id="F2" co-legend-rid="lgnd_F2"><a class="icnblk_img figpopup" href="/pmc/articles/PMC5093089/figure/F2/" target="figure" rid-figpopup="F2" rid-ob="ob-F2"><img src="/pmc/articles/PMC5093089/bin/nihms-753191-f0002.gif" class="small-thumb" alt="Figure 2" title="Fi<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2">learfix" id="F2learfixlearfix" id="F2" co-legend-rid="lgnd_F2"><a class="icnblk_img figpopup" href="/pmc/articles/PMC5093089/figure/F2/" target="figure" rid-figpopup="F2" rid-ob="ob-F2"><img src="/pmc/articles/PMC5093089/bin/nihms-753191-f0002.gif" class="small-thumb" alt="Figure 2" title="Figure 2" src-large=<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2">learfix" id="F2learfixlearfix" id="F2" co-legend-rid="lgnd_F2"><a class="icnblk_img figpopup" href="/pmc/articles/PMC5093089/figure/F2/" target="figure" rid-figpopup="F2" rid-<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2">F2"><span>FigurF2"><spF2"><span>Figure 2F</span></a>, right). Thus, our binding experiments with purified proteins confirmed that both cREL RHbind not only to their own consensus sequences, but also to the other DNA REs, supporting the binding to motifs identified in the ChIP-seq experiment.bindbind nbind not only to their owbind not only to their own consensus sequences, but also to the other DNA REs, supporting the binding to motifsbind bind not only to their own consensus sequences, but also to the other DNA REs, supporting the binding to motifs identified in the ChI<a href="#SD7" rid="SD7" class=" supplementary-material">bind not bind not only to their own consensus sequences, but also to the other DNA REs, supporting the binding to motifs identified in the ChIP-seq experiment.</p></div><div id="S6" class="sec"><h3<a href="/pmc/articles/PMC5093089/figure/F3/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F3" rid-ob="ob-F3" co-legend-rid="lgnd_F3">bind not only to bind nobind n<a href="#SD13" rid="SD13" class=" supplementary-material">bind notbind not only to their own consensus sequences, but also to the other DNA REs, supporting the <a href="/pmc/articles/PMC5093089/figure/F3/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F3" rid-ob="ob-F3" co-legend-rid="lgnd_F3">bind not only to tbind nobind not only to their own consensus sequences, but also to the other DNA REs, su<a href="/pmc/articles/PMC5093089/figure/F3/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F3" rid-ob="ob-F3" co-legend-rid="lgnd_F3">bind not only tbind nobind not only to their own consensus sequences, but also to the other DNA REs, supporting the binding to motifs identified in the ChIP-seq experiment.</p></div><div id="S6" class="sec"><h3>Validati<a href="/pmc/articles/PMC5093089/figure/F3/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F3" rid-ob="ob-F3" co-legend-rid="lgnd_F3">bind not only tbind nobind n<a href="#SD14" rid="SD14" class=" supplementary-material">aterial"aterial">Table S3</a>). We observed a relatively stronger basal TAp73 binding activity when compared with p63α binding, consistent with the ChIP-seq and ChIP-qPCR results. Interestingly, the oligonucleotide containing a predicted AP-1 motif (p21-c) without the other motifs also exhibited TAp73 binding. These binding activities detected by ChIP-seq were validated by two different experimental methods. Thus our current study provided evidence for the co-localization of cREL, ΔNp63 and TAp73 to multiple target promoters and response elements in response to TNF-α, consistent with our previo<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401338">aateria<a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401282">aateriaateraterial">Tableaterial">Table S3</a>). Weaterial">Table S3</a>). We observed a relatively stronger basal TAp73 binding activity wh<a class="icnblk_img figpopup" href="/pmc/articles/PMC5093089/figure/F3/" target="figure" rid-figpopup="F3" rid-ob="ob-F3"><img src="/pmc/articles/PMC5093089/bin/nihms-753191-f0003.gif" class="small-thumb" alt="Figure 3" title="Figure 3" src-large="/pmc/articles/PMC5093089/bin/nihms-753191-f0003.jpg" />ateraterial">Table S3</a>). We observed a rateri<a class="figpopup" href="/pmc/articles/PMC5093089/figure/F3/" target="figure" rid-figpopup="F3" rid-ob="ob-F3">aterial"aterateriaaterial">Table S3ateriateriaaterial">Table S3aterial">Table S3</a>). We observed a relatively stronger basal TAp73 binding activitaterial">aterialateriaateriaateriaateriaaterial">Table S3</a>). Waterial">Table S3</a>). We observed a relatively stronger basal TAp73 binding activity when compareateriaterial">Table S3</a>). We observed a relatively stronger basal TAp73 binding activity when compared with p63α binding, consistent with the ChIP-seq and ChIP-qPCR results. Interestingly, the oligonucleotide containing a predicted AP-1 mo<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4"> class="fig-tab class= class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4"><span>Figure 4A</span></a>). Overexpr<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4"> class="fig-tab class= class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4"><span>Figure 4A</span></a>). Overexpressed TAp73 was a strong inducer of classical TP53 RE reporter activity, which was down-modulated by TNF-α (<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob class="fig-tabl class="fig-table-link fig figpo class="fig- class="fig-table-link f class=" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4"> class="fig-tab class= class="fig-table-link fig figpopup" rid-figpopup="F4" r class="fig-tabl class="fi class="fig- class="fig-table-link fig figpopup" rid-figpopup="F4" rid- class=" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4"><span>Figure 4A</span></a>). Overexpressed TAp73 was a strong inducer of classical TP53 RE reporter activity, which was down-modulated by TNF-α (<a h cla class="fig-ta class="fig-table-link fig class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd<a class="icnblk_img figpopup" href="/pmc/articles/PMC5093089/figure/F4/" target="figure" rid-figpopup="F4" rid-ob="ob-F4"><img src="/pmc/articles/PMC5093089/bin/nihms-753191-f0004.gif" class="small-thumb" alt="Figure 4" title="Figure 4" src-large="/pmc/articles/PMC5093089/bin/nihms-753191-f0004.jpg" />0930093089/bin/nihms-753191-f0004.gif" clas09308<a class="figpopup" href="/pmc/articles/PMC5093089/figure/F4/" target="figure" rid-figpopup="F4" rid-ob="ob-F4">093089/b0930093089093089/bin/nihms-09308093089093089/bin/nihms-093089/bin/nihms-753191-f0004.gif" class="small-thumb" alt="Figure 4" title="Figure 4" src-large="/pmc/articles/PMC5093089/bi093089/093089093089093089093089/bin/nihms-753191-f0004.gif" class="small-thumb" alt="Figure 4" title="Figure 4" src-large="/pmc/articles/PMC5093089/bin/nihms-753191-f0004.jpg" /></a><div class="icn<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5">093089/bin/nih093089/093089/bin/nihm<a href="#SD7" rid="SD7" class=" supplementary-material">093089/bi093089<a href="#SD8" rid="SD8" class=" supplementary-material">09093089/bin/nihms-753191-f0004.gif" class="small-thumb" al093089/bin/093089/bin/nihms-753191-f000<a href="#R13" rid="R13" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401362">09093089/bin/nihms-753191-f0004.g093089/bi093089/bin093089/bin/n093089/<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4">093089/bin/nihm093089/093089/bin/nihms-7531093089/bi093089/bin/nihms-753191-f0004.gif" class="small-thumb" alt="Figure<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4">093089/bin/nihm093089/093089/bin/nihms-753191-f0004.gif" class="s093089/bin093089/bin093089/bin/nihms093089/bin/nihms-753191-f0004.gif" class="small-thumb" alt="Figure 4" title="Figure 4" src-large="/pmc/articles/PMC5093089/bin/nihms-753191-f0004.jpg" /></a><div class="icnblk_cntnt" id="lgnd_F4"><div><a class="figpopup" href="/pmc/articles63α, and TAp73 can differentially regulate a functionally diverse gene repertoire.63?α, a63α, and TAp73 can63α, and TAp73 can differentially regulate a functionally diverse gene repertoire<a class="icnblk_img figpopup" href="/pmc/articles/PMC5093089/figure/F5/" target="figure" rid-figpopup="F5" rid-ob="ob-F5"><img src="/pmc/articles/PMC5093089/bin/nihms-753191-f0005.gif" class="small-thumb" alt="Figure 5" title="Figure 5" src-large="/pmc/articles/PMC5093089/bin/nihms-753191-f0005.jpg" />63?α, and TAp73 can differential63&#x<a class="figpopup" href="/pmc/articles/PMC5093089/figure/F5/" target="figure" rid-figpopup="F5" rid-ob="ob-F5">63ͣ?cα, and 63ccα, and 63α, and TAp73 can differentially regulate a functionally diverse gene repertoire.</p><!--fig ft0--><63㭣cccccα, and TAp73 ca63α, and TAp73 can differentially regulate a functionally diverse gene repertoire63cα, and TAp73 can differentially regulate a functionally diverse gene repertoire.</p><!--fig ft0--><!--fig mode=article f1--><div class="fig iconblock ten_col whol<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5">63α, a63cα, and TAp73 can differentially regulate a functionally diverse gene repertoire.</p><!--fig ft0--><!--fig mode=article f1--><div class="fig iconblock ten_col whole_rhythm clearfix" id="F5" co-legend-rid="lgnd_F5"><a class="icnblk_img figpopup" href="/pmc/articles/PMC5093089/figure/F5/" target="figure" rid-figpopup="F5" rid-ob="ob-F5"><img src="/pmc/articles/PMC5093089/bin/nihms-75<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5">63α, and T63cα, and TAp73 can differentially regulate a functionally diverse gene repertoire.</p><!--fig ft0--><Chi-square, up-regulated genes, p=4.3E-07; down-regulated genes, p=5.5E-05). The numbers of differentially expressed genes with individual or overlapping binding activities for the three TFs are presented for basal activities (<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5"> activities (<a activi activities (<a href="/pmc/articles/PMC5093089<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5"> activities (<a activi activities (<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-ri<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5"> activities (<a hr activi activities (<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5"><span>Figure 5C</span></a>), or TNF-α modulated activities (<a href="/pmc/arti<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5"> activities (<a activi activities (<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5"><span>Figure 5C</span<a href="#SD8" rid="SD8" class=" supplementary-material"> activiti activities (<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5"><span>Figure 5C</span></a>), or TNF-;<a href="#SD15" rid="SD15" class=" supplementary-material"> activiti activiti<a href="#SD16" rid="SD16" class=" supplementary-material"> a activities (<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5"><span>Figure 5C</span></a>), or TNF-; act activ activities (<a href="/pm activities (<a hr;Np63, and TAp73 expression and altered gene and protein signatures in HNSCC tissues and ΔNp63α transgenic mouse skin;Np63;Np63, and TAp73 expression and altered gene and protein signatures in HNSCC tissues and ΔNp63α transgenic mouse skin</<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5">;Np63, and TAp7;Np63, ;Np63, and TAp73 expression and altered gene and protein signatures in HNSCC tissues and ΔNp63α transgenic mouse skin</h3><p id<a href="#R1" rid="R1" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401292">;;Np63, and TAp73 expression and altered gene and protein signatures in HNSCC tissues and ΔNp63α transgenic mouse skin</h3><p id="P14" class="p p-first">We examined the 46 TNFα-upregula<a href="/pmc/articles/PMC5093089/figure/F6/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F6" rid-ob="ob-F6" co-legend-rid="lgnd_F6">;Np63, and TAp7;Np63, ;Np63, and TAp73 expression and altered gene and protein signatures in HNSCC tissues and ΔNp63α transgenic mouse skin</h3><p id="P14" class="p p-first">We examined the 46 TNFα-upregulated genes and 27 down-regu<a href="#SD18" rid="SD18" class=" supplementary-material">;Np63, a;Np63, and TAp73 expression and altered gene and protein signatures in HNSCC tissues and ΔNp63α transgenic mouse skin</h3><p id="P14" class="p p-first">We examined the 46 TNFα-upregulated genes and 27 down-regulated genes co-bound by all 3 r all 73 genes confirms that many of the TNFα inducible and down-regulated genes in cell lines co-cluster among 4 major tumor subsets (<a href="#SD9" rid="SD9" class=" supplementary-material">r all 73 r all 73 genes confirms that many of the TNFα inducible and down-regulated genes in cell lines co-cluster among 4 major tumor subsets (<a href="#SD9" rid="SD9" cr all 73 genes confirms that many of the TNFα inducible and down-r all 73 genes confirms that many of the TNFα inducible and down-regulated genes in cell liner all 7r all 73 gr all 73 genr all 73 genes confirms that many of the TNFα inducible and dr all 73 genr all 73 genes confirms that many of r all 7r all 73 genes co<a href="#R14" rid="R14" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401264">r r all<a href="#R17" rid="R17" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401344">r r all r alr all 73 genesr all 73 genes confirms thr all 73 genes confirms that many of the TNFα inducible and down-regulated genes <a class="icnblk_img figpopup" href="/pmc/articles/PMC5093089/figure/F6/" target="figure" rid-figpopup="F6" rid-ob="ob-F6"><img src="/pmc/articles/PMC5093089/bin/nihms-753191-f0006.gif" class="small-thumb" alt="Figure 6" title="Figure 6" src-large="/pmc/articles/PMC5093089/bin/nihms-753191-f0006.jpg" />r alr all 73 genes confirms that many of thr all<a class="figpopup" href="/pmc/articles/PMC5093089/figure/F6/" target="figure" rid-figpopup="F6" rid-ob="ob-F6">r all 73r alr all r all 73 genes cor allr all r all 73 genes cor all 73 genes confirms that many of the TNFα inducible and down-regulated genes in cell lines co-cluster among 4 major tumor subsets (<a href="#SD9" rid="SD9" class=" r all 73 r all 7r all r all r all r all 73 genes confirms that many of the TNFα inducible and down-regulated genes in cell lines co-cluster among 4 major tumor subsets (<a href="#SD9" rid="SD9" class=" supplementary-material">Figure S8</a>, clusters a-d). Among t<a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401334">RR8" class=" bibr study of TNF-α modulated genes (<a href="#SD8" rid="SD8" class=" supplementary-material"> study of study of TNF-α<a href="#SD11" rid="SD11" class=" supplementary-material"> study of TNF- study of TNF-α modulated genes (<a href="#SD8" rid="SD8" class=" supplementary-material">Figure S7</a>), as described in <a href="#SD11" rid="SD11" class=" supplementary-material">supplemental Methods</a>. An expression-based method was used to cluster a group of genes with common profiling patterns and TP63 transcription factor moti<a href="#R18" rid="R18" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401317"> s stud<a href="#R20" rid="R20" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401293"> s study of TNF-α modulated genes (<a href="#SD8" rid="SD8" class=" supplementary-material">Figure S7</a>), as described in <a href="#SD11" rid="SD11" class=" supplementary<a href="/pmc/articles/PMC5093089/figure/F6/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F6" rid-ob="ob-F6" co-legend-rid="lgnd_F6"> study of TNF-& study study of TNF-α modulated genes (<a href="#SD8" rid="SD8" class=" supplementary-material">Figure S7</a>), as described in <a href="#SD11" study of TNF-α modulated g study of TNF-α modulated genes study of TNF-α modulat study of TNF-α modulat study of TNF-� study of TNF-α modulated genes (<a href="#SD8" rid="SD8" class=" supplementary-material">Figure S7</a>), as described in <a href<a href="#SD9" rid="SD9" class=" supplementary-material"> study of study of TN study of TNF-α modulated genes (<a hre study stu study of TNF-α modulated genes (<a href="#SD8" rid="SD8" class=" supplementary-material">Figure S7</a>), as described in <a href="#SD11" rid="SD11" class=" supplementary-material">supplemental Methods</a>. An expression-based method was used to cluster a gr<a href="#R21" rid="R21" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401354"> s study<a href="#R22" rid="R22" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401279">"#"#R22" rid="R22" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401279">22</a>). Array profiling detected increased expression of a panel of up"#R22" ri"#R22" rid"#R22" r"#R22" rid="R22" class=" bibr popnode tag_h"#R22" ri"#R22" <em>Ik <em>Ikk</em> <em>Ikk <em>Ikk</em>ε and <em>Relb <em>Ikk <em>Ikk</e <em>Ikk</em <em>Ik<a href="/pmc/articles/PMC5093089/figure/F6/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F6" rid-ob="ob-F6" co-legend-rid="lgnd_F6"> <em>Ikk</em>&# <em>Ik <em>I <em <em>Ikk</em>ε and <em>Relb</em>, and their downstream genes, <em>Il-6</em>, and <em>Serpine1</em> (<a href="/pmc/articles/PMC5093089/figure/F6/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F6" rid-ob="ob-F6" co-legend-rid="lgnd_F6"><span>Figure 6C</span></a>).</p><p id="P17" class="p p-last">We next validated if proteins of TNF-α co-modulated TFs and four target genes identified in multiple platforms above, display corresponding alterations in human HNSCC tumor and tissue arrays. The nuclear-cytoplasmic dis<a href="/pmc/articles/PMC5093089/figure/F6/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F6" rid-ob="ob-F6" co-legend-rid="lgnd_F6"> <em>Ikk</em>&# <em>Ik <em>I<a href="#SD10" rid="SD10" class=" supplementary-material"> < <em>Ikk</em>ε and <em>Relb</em>, and their downstream genes, <em>Il-6</em>, and <em>Serpine1</em> ( <em>Ikk</em <em>Ikk<<a href="/pmc/articles/PMC5093089/figure/F1/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1"> <em>Ikk</em>� <em>Ik <em>Ikk</em>ε an<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401308"> <em>Ik<a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401280"> <em>Ikk</em>ε and <em>Relb</em>, and their downstream genes, <em>Il-6</em>, and <em>Serpine1</em> (<a href="/pmc/articles/PMC5093089/figure/F6/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F6" rid-ob="ob<a href="#SD11" rid="SD11" class=" supplementary-material"> <em>Ikk</em>; <em>Ikk</em>ε and <em>Relb<scription factor targets scriptioscription scriptionscription factor targets <em>JUNB</em> and <em>FOSL1</em>, showed significantly elevated n<a href="/pmc/articles/PMC5093089/figure/F6/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F6" rid-ob="ob-F6" co-legend-rid="lgnd_F6">scription factoscriptiscription factor targets <em>JUNB</em> and <em>FOSL1</em>, showed signiscriptioscription scriptionscription factor targe<a href="/pmc/articles/PMC5093089/figure/F3/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F3" rid-ob="ob-F3" co-legend-rid="lgnd_F3">scription factoscriptiscrip<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5">scription factor targets <em>JUNB</em> and <em>FOSL1</em>, showscription factor targets <em>JUNB</em> and <em>FOSL1</em>, showescriptiscriptiscriptiscriptiscription factor targets <em>JUNB</em> ascriptioscription scriptionscription factor targets <em>JUNB</em> and <em>FOSL1</em>, s<a href="/pmc/articles/PMC5093089/figure/F6/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F6" rid-ob="ob-F6" co-legend-rid="lgnd_F6">scription factoscriptiscription factor targets <em>JUNB</em> and <em>FOSL1</em>, showed significantly elevated nuclear staining in HNSCC tumors relative to mucosa (<a href="/pmc/articles/PMC5093089/figure/F6/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F6" rid-ob="ob-F6" co-legend-rid="lgnd_F6"><span>Figure 6E</span></a>), consistent with altered AP-1 promscription factscription factor targets <em>JUNB</em> and <em>FOSL1</em>, showescription fascription scription fscription factscriscriptscription factor targets <scription factor targets <em>JUNB</em> and <em>FOSL1</em>, showed significantly elevated nuclear staining in HNSCscripscription factor targets <em>JUNB</em> and <em>FOSL1</em>, showed significantly elevated nuclear staining in HNSCC tumors relative to mucosa (<a href="/pmc/articles/PMC5093089hich identified inflammatory as well as a “TP53-like” compensatory gene expression activity pattern associated with increased ΔNp63 and TP73 activities, and frequent genomic inactivation of TP53 in the squamous-like tumors (<a href="#R2" rid="R2" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401324">hhich identified inflammatory as well as a “TP53-like” compensatory gene expression activity pattern associated with increased ΔNp63 and TP73 activities, and frequent genomic inactivation of TP53 in the squam<a href="/pmc/articles/PMC5093089/figure/F7/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F7" rid-ob="ob-F7" co-legend-rid="lgnd_F7">hich identifiedhich idhich identified inflammatory as well as a “TP53-like” compensatory gene expression activity pattern associated with increased ΔNp63 and TP73 activities, and frequent genomic inactivation of TP53 in the squamous-like tumors (<a href="<a href="#R23" rid="R23" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401262">hihich i<a href="#R24" rid="R24" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401277">hihich identified inflammatory as well as a “TP53-like” compensatory gene expression activity pattern associated with increased ΔNp63 and TP73 activities, and frequent genomic inactivation of TP53 in the squamous-like tumors (<a href="#R2" rid="R2" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401324">2</a>). These squamous cancers included 293 HNSCC, 156 lung SCC and 24 bladder SCC, which were analyzed for TP53/63/73 status and expression and function of 8 genes identified among their known and new targets in the present study. <a href="/pmc/articles/PMC5093089/figure/F7/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F7" rid-ob="ob-F7" co-legend-rid="lgnd_F7"><span>Figure 7A</span></a> shows CircleMaps, which enable a mhich identified inflammahich identified inflammatory as wellhichMET, MAP4K4MET, MAP4K4</em>), transcriptioMET, MAP4K4</em>), trMET, MAP4K4</em>), transcriptiMET, MAP4K4</em>)MET, MAP4K4</em>), transcription factors (<em>AP-1/FOSL1, CEBPA</em>), and secreted factors (<em>SERPINE1, IL6</em>). The expression and Per cancer types. By Pearson correlation analysis (<a href="/pmc/articles/PMC5093089/figure/F7/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F7" rid-ob="ob-F7" co-legend-rid="lgnd_F7">er cancer typeser cancer cancer types. By Pearson correlation analysis (<a href="/pmc/articles/PMC5093089/figure/F7/" target="figure" class="fig-taer cancer types. By Pearson corer cancer ter cancer er cancer types. By Pearson correlation analysis (<a href="/pmc/articles/PMC5093089/figure/F7/" taer cancerer cancer types. By Pearson correlation analysis (<a <a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4">er cancer types.er cancer can<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5">er cancer types. By Pearson correlation analysis (<a href="/pmcer cancer types. By Pearson correlation analysis (<a href="/pmc/aer cancer cancer canceer cancer cancer types. By Pearson correlation analysis (er cancer cancer types. By Pearson correlation analysis (<a href="/pmcer cancer types.er cancer types. By Pearson<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4">er cancer typeser cancer cancer cancer tyer cancer types. By Pearson correlation analysis (<a href="/pmc/articles/PMC5093089/figure/F7/" target="figure" class="fig-table-link<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4">er cancer types. Ber cancer caner cer cancer typeer cancer types. By Pearsoer cancer types. By Pearson correlation analysis (<a href="/pmc/articles/PMC5093089/figur<a class="icnblk_img figpopup" href="/pmc/articles/PMC5093089/figure/F7/" target="figure" rid-figpopup="F7" rid-ob="ob-F7"><img src="/pmc/articles/PMC5093089/bin/nihms-753191-f0007.gif" class="small-thumb" alt="Figure 7" title="Figure 7" src-large="/pmc/articles/PMC5093089/bin/nihms-753191-f0007.jpg" />k_imk_img figpopup" href="/pmc/articles/PMCk_img<a class="figpopup" href="/pmc/articles/PMC5093089/figure/F7/" target="figure" rid-figpopup="F7" rid-ob="ob-F7">k_img fik_imk_img k_img figpopup" hk_imgk_img k_img figpopup" hk_img figpopup" href="/pmc/articles/PMC5093089/figure/F7/" target="figure" rid-figpk_img figk_img fk_img k_img k_img k_img k_img figpopup" href="/pmc/articlesk_img figpopup" href="/pmc/articles/PMC5093089/figure/F7/" target="figure" rid-figpopup="F7" rid-ob="obk_imgk_img figpopup" href="/pmc/articles/PMC5093089/figure/F7/" target="figure" rid-figpopup="F7" rid-ob="ob-F7"><img src="/pmc/articles/PMC5093089/bin/nihms-753191-f0007.gif" class="small-thumb" <a href="/pmc/articles/PMC5093089/figure/F3/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F3" rid-ob="ob-F3" co-legend-rid="lgnd_F3">k_img figpopup"k_img fk_img<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5">k_img figpopup" href="/pmc/articles/PMC5093089/figure/F7/" targk_img figpopup" href="/pmc/articles/PMC5093089/figure/F7/" targk_img fk_img fk_img fk_img fk_img f<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401331">kk_img <a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401329">kk_img <a href="#R25" rid="R25" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401314">k_k_img figpopup" href="/pmc/articles/PMC5093089/figure/F7/" target="figure" rid-figpopup="F7" rid-ob="ob-F7"><img src="/pmc/articles/PMC5093089/bin/nihms-753191-f0007.gif" cla<a href="#R2" rid="R2" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401346">kk_img figpopup" href="/pmc/as) linking TP63 and NF-κB family members and target genes has not been well elucidated. We thus searched within the interconnected network of differentially activated PARADIGM pathways, linked through regulatory hubs with >15 downstream targets, derived from a larger interconnected network displaying differentially activated proteins inferred between the C2-Squamous-like subtype and other tumors, as detailed in <a href="#SD11" rid="SD11" class=" supplementary-material">s) linking TP63 and s) lin<a href="#SD17" rid="SD17" class=" supplementary-material">s) linkis) lin<a href="#SD2" rid="SD2" class=" supplementary-material">s) linkings) lin<a href="#R26" rid="R26" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401345">s)s) linking TP63 and NF-κB family members and target genes has not been well elucidated. We thus searched within the interconnected network of differentially activated PARADIGM pathways, linked through re<a href="/pmc/articles/PMC5093089/figure/F7/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F7" rid-ob="ob-F7" co-legend-rid="lgnd_F7">s) linking TP63s) links) linking TP63 and NF-κB family members and target genes has not been well elucidated. We thus searched within the interconnected network of differentially activated PARADIGM pathways, linked through regulatory hubs with >15 downstream targets, derived from a s) linking Ts) linkings) linking s) link<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2">s) linking TP6s) links) li<a href="/pmc/articles/PMC5093089/figure/F6/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F6" rid-ob="ob-F6" co-legend-rid="lgnd_F6">s) linking TP63 and NF-κB family members and target gens) linking TP63 and NF-κB family members and target genes) links) links) links) links) linking TP63 and NF-κB family members and target genes has not been well elucidated. ated previously, such as TP63 regulated ated previously, such as TP63 regulated <em>CDKN1A, ated previously, such as TP63 regulated <em>CDKN1A, GADated previously, ated previously, such as TP63 regulated <em>CDKN1A, GADD45A, IL1A, CHUK, YAP1, IGFBP3, KRT14</em>; as well as NF-κB and AP-1 related genes <em>IL-6 and IL-8</em>, and MAPK1/ERK/JUN/FOSand pathways. Most of these related genes in squamous cancers are activated (red) when compared with other cancer types. Furthermore, a more extended network connecting ΔNp63α,<a href="#SD2" rid="SD2" class=" supplementary-material">ated previoated previously, such as TP63 regulated <em>CDKN1A, GADD45A, IL1A, CHUK, YAP1, IGFBP3, KRT14</em>; as well a<a href="#SD2" rid="SD2" class=" supplementary-material">ated previousated previously, such as TP63 regulated <em>CDKN1A, GADD45A, IL1A, CHUK, YAP1, IGFBP3, KRT14</em>; as well as NF-κB and AP-1 related genes <em>IL-6 and IL-8</em>, and MAPK1/ERK/JUN/FOSand pathways. Most of these related genes in squamous<a href="#SD17" rid="SD17" class=" supplementary-material">ated preated atedated pated pated previously, such as TP63 rated previously, such as TP63 regulated <em>CDKN1A, GADD45ated ated previously, such as TP63 regulated <em>CDKN1A, GADD45A, IL1A, CHUK, YAP1, IGFBP3, KRT14</em>; as well as NF-κB and AP-1 related genes <em>IL-6 and IL-8</em>, and MAPK1/ERK/JUN/FOSand pathways. Most of these related genes in squamous cancers are activated (red) when compared with other cancer types. Furthermore, a more extended network connecting ΔNp63α, TP53 and AP-1 transcription complexes (among other regulatory hubs), links a larger number of target genes identified in t<a href="/pmc/articles/PMC5093089/figure/F8/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F8" rid-ob="ob-F8" co-legend-rid="lgnd_F8">ated previouslated prated previously, such as TP63 regulated <em>CDKN1A, GADD45A, IL1A, CHUK, YAP1, IGFBP3, KRT14</em>; as wellflammatory gene programs, which helps explain the finding of unique TP63/TP73 gene signatures compensating for mutant TP53 identified recently in squamous cancers from TCGA HNSCC and PanCancer projects (<a href="#R1" rid="R1" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401310">fflamma<a href="#R2" rid="R2" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401330">fflammatory gene programs, which helps explain the finding of unique TP63/TP73 gene signatures compensating for mutant TP53 identified recently in squamous cancers from TCGA HNSCC and PanCancer projects (<a <a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401347">f</a>, <a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401313"><</a>, <a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401313">8</a>). Our studies showed that these transcription factors regulate genes involved in several aspects of cell fate including cell proliferation, stemness, survival/apoptosis, and migration, as well as, epithelial cell growth, inf<a href="#R27" rid="R27" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401275"></</a>, <a href="#R28" rid="R28" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401299"></</a>, </a></a>, <a href=</a>, <a href="#R8" rid="R</a>, <a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_5694<a class="icnblk_img figpopup" href="/pmc/articles/PMC5093089/figure/F8/" target="figure" rid-figpopup="F8" rid-ob="ob-F8"><img src="/pmc/articles/PMC5093089/bin/nihms-753191-f0008.gif" class="small-thumb" alt="Figure 8" title="Figure 8" src-large="/pmc/articles/PMC5093089/bin/nihms-753191-f0008.jpg" /></a></a>, <a href="#R8" rid="R8" class=" bi</a>,<a class="figpopup" href="/pmc/articles/PMC5093089/figure/F8/" target="figure" rid-figpopup="F8" rid-ob="ob-F8"></a>, <a</a></a>, </a>, <a href="#R</a>,</a>, </a>, <a href="#R</a>, <a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401313">8</a>). Our studies3 chromatin occupancy and reprogramming of TAp73 from TP53 to AP-1 sites to promote inflammatory and cancer gene programs3 chromat3 chrom3 chro3 chro3 chro3 chromatin occupancy and reprogramming of TAp73 from TP53 to AP-1 sites to promote inflammatory and cancer gene programs</strong></span></div></div></div><p id="P21">After cross comparison of 12 different cancer types, TCGA PanCancer 12 project un<a href="#R2" rid="R2" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401286">33 chromatin occupancy and reprogramming of TAp73 from TP53 to AP-1 sites to promote inflammatory and cancer gene programs</strong></span></div></div></div><p id="P21">After cross comparison of 12 different cancer types, TCGA PanCancer 12 project uncovered several unique signatures that differentiate squamous cancers from other cancer types, such as high rates of TP53 mutation and TP63 ampl<a href="#R23" rid="R23" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401285">3 3 chro3 ch3 chromatin occupancy and reprogramming of TAp73 from TP53 to AP-1 sites to promote inflammatory and cancer gene programs</strong></span></div></div></div><p id="P21">After cross comparison of 12 different cancer ty<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401349">33 chro<a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401352">33 chromatin occupancy and reprogramming of TAp73 from TP53 to AP-1 sites to promote inflammatory and cancer gene programs</strong></span></div></div></div><p id="P21">After cross comparison of 12 different cancer types, TCGA PanCancer 12 project uncovered several unique signatures that differentiate squamous cancers from other ca<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401363">33 chromatin occupancy and reprogramming of TAp73 from TP53 to AP-1 sites to promote inflammatory and cancer gene programs</strong></span></div></div></div><p id="P21">After cross comparison of 12 different cancer types, TCGA PanCanceEL/NF-κB. Such TP63/TP73 compensatory TP53 function has been associated with higher sensitivity to cisplatin chemotherapy in both HNSCC (<a href="#R29" rid="R29" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401357">ELEL/NF-<a href="#R30" rid="R30" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401270">ELEL/NF-κB. Such TP63/TP73 compensatory TP53 functio<a href="#R31" rid="R31" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401315">ELEL/NF-κB. Such TP63/TP73 compensatory TP53 function has been associated with higher sensitivity to cisplatin chemotherapy in both HNSCC (<a href="#REL/NEL/NF-κB. Such TP63/TP73 compensatory TP53 function has been associated with higher sensitivity to ci<a href="#R1" rid="R1" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401297">EEL/NF-κB. Such TP63/TP73 compensatory TP53 function has <a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401289">EEL/NF-κB. Such TP63/TP73 compensatory TP53 function has been associated with higher sensitivity to cisplatin chemotherapy in both HNSCC (<a href="#R29" rid="R29" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401357">29</a>, <a href="#R30" rid="R30" class=" bibr poEL/NF-κB. SuchEL/NF-L/NF-&#EL/NF-κB. Such TP63/TP73 compensatory TP53 function has been associated with higher sensitivity to cisplatin chemotherapy in both HNSCC (<a href="#R29" rid="R29" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401357">29</a>, <a href="#R30" rid="R30" class=" bibr popnode tag_hotlink tag_tooltip" i<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401294">EEL/NF-κB. Such TP63/TP73 compensatory TP53 function has been associated with higher sensitivity to cisplatin chemotherapy in both HNSCC (<a href="#R29" rid="R29" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401357">29</a>, <a href="#R30" rid="R30" class=" <a href="#R32" rid="R32" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401306"> b bibr <a href="#R33" rid="R33" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401272"> b bibr bib bibr popnode tag_hotlink tag_tooltip" id="__tag_569401306">32</a>, <a href="#R33" rid="R33" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401272">33</a>).</p><p id="P24">Our prior and current findings help further clarify the apparent function of TP63/TP73 bibr popnode ta bibr popn bibr popno bibr popnode tag_hotlink tag_too<a href="#R9" rid="R9" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401319"> bibr <a href="#R30" rid="R30" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401290"> b bibr popnode tag_hotlink tag_tooltip" id="<a href="/pmc/articles/PMC5093089/figure/F3/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F3" rid-ob="ob-F3" co-legend-rid="lgnd_F3"> bibr popnode bibr p bibr<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5"> bibr popnode tag_hotlink tag_tooltip" id="__tag_569401306">32< bibr popnode tag_hotlink tag_tooltip" id="__tag_569401306">32</ bibr p bibr p bibr p bibr p bibr popnode tag_hotlink tag_tooltip" id="__tag_569<a href="/pmc/articles/PMC5093089/figure/F6/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F6" rid-ob="ob-F6" co-legend-rid="lgnd_F6"> bibr popnode t bibr p bibr popnode tag_hotlink tag_tooltip"<a href="/pmc/articles/PMC5093089/figure/F7/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F7" rid-ob="ob-F7" co-legend-rid="lgnd_F7"> bibr popnode bibr p bibr popnode tag_hotlink tag_tooltip" id="__tag_569401306e TAp73, attenuating its TP53 compensatory function, while also enhancing a much broader oncogene program implicated in cancer promotion (<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401356">ee TAp7<a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401360">ee TAp73, attenuating its TP53 compensatory function, while also enhancing a much broader oncogene program implicated in cancer promotion (<a href="#R6" rid="R6" class=e TAp73, e TAp73,<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4">e TAp73, attene TAp73e TAp<a href="/pmc/articles/PMC5093089/figure/F6/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F6" rid-ob="ob-F6" co-legend-rid="lgnd_F6">e TAp73, attenuating its TP53 compensatory function, while alsoe TAp73, attenuating its TP53 compensatory function, while also enhance TAp73e TAp73e TAp73e TAp73e TAp73, attenuating its TP53 compensatory function, while also enhancing a much broader oncogene program implicated in cancer promotion (<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401356">6</a>, <a href="#R8" rid="R8<a href="#R2" rid="R2" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401318">ee TAp73, attenuating its TP53 compensatory function, while also enhancing a much broader oncogene program implicated in cancer promotion (<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="_<a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401326">ee TAp73, attenuating its TP53 compensatory function, while also enhancing a much broader oncogene program implicated in cancer promotion (<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401356">6<<a href="#R2" rid="R2" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401302">ee TAp73, attenuating its TP53 compensatory function, while also enhancrogram TP73 tumor suppressor to oncogenic activity, through binding to AP-1 sites, as supported by ChIP seq, ChIP RT-PCR, and binding assays (<a href="/pmc/articles/PMC5093089/figure/F1/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F1" rid-ob="ob-F1" co-legend-rid="lgnd_F1">rogram TP73 t11</span1</sp<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4">1</span></a>-<a href="/pmc/articles/PMC5093089/figure/F4/" targ1</span></a>-<a href="/pmc/articles/PMC5093089/figure/F4/" targ1</span1</span1</span1</span1</span></a>-<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4"><span style="position: relative;text-decoration:none;">​<span class="figpopup-sensitive-area" style="left: -0.<a href="/pmc/articles/PMC5093089/figure/F7/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F7" rid-ob="ob-F7" co-legend-rid="lgnd_F7">1</span></a>-<a1</span1</span><<a href="#SD2" rid="SD2" class=" supplementary-material">1</span></1</spa1</s1</span></a>-<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4"><span style="position: relative;text-decoration:none;">​<span class="figpopup-sensitive-area" style="left: -0.5em;">-4)</span></span><span>4</span></a>) in this study. This novel finding is also supported by the PanCancer 12 data indicating that inflammatory gene signatures linked by cytokine TNF-α and NF-κB transcription factors are connecte<a href="#R34" rid="R34" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401269">1<1</span></a>-<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4"><span style="position: relative;text-decor<a href="#R35" rid="R35" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401281">1<1</span></a>-<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-t<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2"><span>Figure 2an>Figuan>Figure 2</span></a>), which are similar to the sequences of TP53/TP63/TP73 and nearby AP-1 binding motifs observed in <a href="#R34" rid="R34" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401304">anan>Fi<a href="#R39" rid="R39" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401273">anan>Figure 2</span></a>), which are similar to the sequences of TP53/TP63/TP73 and nearby AP-1 binding motifs observed in previous studies (<a href="#R34" rid="R34" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401304"<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401359">aan>Figure 2</span></a>), which are similar to the sequences of TP53/TP63/TP73 a<a href="#R9" rid="R9" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401325">aan>Figure 2</span></a>), which are similar to the sequences of TP53/TP63/TP73 and nearby AP-1 binding motifs observed in previous studies (<a href="#R34" rid="R34" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401304">34</a>-<a href="#R39" rid="R39" class=" <a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2">an>Figure 2</span></aan>Figuan>Figure 2</span></a>), which are similar to the sequences of TP53/TP63/TP73 and nearby AP-1 binding motifs observed in previous studies (<a href="#R34" rid="R34" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569an>Fan>Figure 2</span></a>), which are similar to the sequences of TP53/TP63/TP73 and nearby AP-1 binding motifs observed in previous studies (<a href="#R34" rid="R34" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401304">34</<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401283">aan>Fig<a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401353">aan>Figure 2</span></a>), which are similar to the sequences of TP53/TP63/TP73 and nearby AP-1 binding motifs observed in can bind to AP-1 REs independent of ΔNp63α or other cofactors. Our sedimentation velocity centrifugation experiments revealed that both cREL and TP73 bind these DNA REs and can form dimers and/or tetramers upon DNA binding. These results provide biophysical support to the model of co-localized binding of cREL and TP73 suggested by the ChIP-seq and bioinformatics analyses. Collectively, the different experimental approaches provide mechanistic details of how TFs can occupy binding sites at the same as well as very close promoter sequences.can can bind to AP-1 REs independent of ΔNp63α or other cofactors. Our sedimentation velocity centrifugation experiments revealed that both cREL and TP73 bind these DNA REs and can form dimers and/or tetramers u<a href="/pmc/articles/PMC5093089/figure/F4/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F4" rid-ob="ob-F4" co-legend-rid="lgnd_F4">can bind to AP-can bincan bind to AP-1 REs independent of ΔNp63α or other cofactors. Our sedimentation velocity centrifugation experimentscan bind to AP-1can bind to AP-1 REs independent can bindcan bind to AP-1 REs independent of ΔNp63α or other cofactors. Our sedimentation velocity centrifugation experiments revealed that both cREL and TP73 bin<a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401288">ccan bi<a href="#R40" rid="R40" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401263">cacan bind to AP-1 REs inde73α strongly induced 73α stro73𻅳α 73α strongly induced <em>CDKN1A (p21)</em> and <em>SERPINE1</em> reporter ac<a href="#R9" rid="R9" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401358">773�<a href="#R31" rid="R31" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401267">7373�<a href="#R35" rid="R35" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401340">7373�<a href="#R41" rid="R41" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401259">7373�<a href="#R42" rid="R42" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401339">7373α strongly induced <em>CDKN1A (p21)</em> and <em><a href="#R43" rid="R43" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401265">7373�<a href="#R44" rid="R44" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401332">7373α strongly induced <em>CDKN1A (p21)</em> and <em>SERPINE1</em> reporter activity, consistent with its compensatory function for mutant TP53 (<a href="#R9" rid="R9" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401358">9</a>, <a href="#R31" rid="R31" 73Iα strongly induced <em>CDKN1A (p21)</em> and <em>SERPINE1</em> reporter activity, consistent with its compensatory function for mutant TP53 (<a href="#R9" rid="<a href="#R45" rid="R45" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401364">7373�<a href="#R46" rid="R46" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401355">7373α strongly induced <em>CDKN1A (p21)</em> and <em>SERPINE1</em> reporter activity, consistent with its compensatory function for mutant TP53 (<a href="#R9" rid="R9" class=" bibr popnode t<a href="#R2" rid="R2" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401268">773α strongly induced <em>CDKN1A (p21)</em> and <em>SERPINE1</em> reporter activity, consistent with its compensatory function for mutant TP53 (<a href="#R9" rid="R9" class=" bibr popnode tag_73α st73α porters containing AP-1 REs. In addition, porters cporters coporters porters containing AP-1 REs. In addition, <em>FOSL1</em> and <em>JUNB</em> expression were significantly associated with p63 and p73 expression in human HNSCC cells and ΔNp63α transgenic mice. This is consistent with our finding that FOSL/Fra1, cJUN and JUNB are the major AP-1 protein family members expressed and bound to AP-1 sites, and<a href="#R47" rid="R47" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401333">131333"><a href="#R48" rid="R48" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401305">131333">47</a>, <a href="#R48" rid="R48" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401305">48</a>). Our data are supported by others’ o<a href="#R35" rid="R35" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401301">131333"><a href="#R43" rid="R43" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401328">131333"><a href="#R44" rid="R44" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401261">131333">47</a>, <a href="#R48" rid="R48" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401305">48</a>). Our data are supported by others’ observations that p73 and AP-1 family members can enhance each other's binding and transcription activities (<a href="#R35" rid="R35" class=" bib13331333">47</a>, <a href="#R48" rid="R48" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401305">48</a>). Our data are supported by others’ observations that p73 and AP-1 family members can enhance each other's binding and transcription activities (<a href="#R35" rid="R35"<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401327">11333"><a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401312">11333"><a href="#R31" rid="R31" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401295">131333">47</a>, <a href="#R48" rid="R48" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401305">48</a>). Our data are supported by oth<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2">1333">47</a>, <a href="1333">41333"><a href="/pmc/articles/PMC5093089/figure/F3/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F3" rid-ob="ob-F3" co-legend-rid="lgnd_F3">1333">47</a>, <a href="#R48" rid="R48" class=" bibr popnode tag1333">47</a>, <a href="#R48" rid="R48" class=" bibr-0.5em;">,3C).-0.5em;-0.5em;-0.5em;"-0.5em;-0.5em;">,3C).</span></span><span>3C</span></a>). Thirdly, nuclear TAp73 binding is displaced from TP53/p63 sites by the cREL/ΔNp63α complex<a href="/pmc/articles/PMC5093089/figure/F2/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F2" rid-ob="ob-F2" co-legend-rid="lgnd_F2">-0.5em;">,3C).-0.5em;-0.5em<a href="/pmc/articles/PMC5093089/figure/F3/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F3" rid-ob="ob-F3" co-legend-rid="lgnd_F3">-0.5em;">,3C).</span></span><span>3C</span></a>). Thirdly, nucl-0.5em;">,3C).</span></span><span>3C</span></a>). Thirdly, nuc-0.5em;-0.5em;-0.5em;-0.5em;-0.5em;<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401307">--0.5em;">,3C).</span></span><span>3C</span></a>). Thirdly, nuclear TAp73 binding is displaced from TP53/p63 sites by the cREL/&<a href="/pmc/articles/PMC5093089/figure/F5/" target="figure" class="fig-table-link fig figpopup" rid-figpopup="F5" rid-ob="ob-F5" co-legend-rid="lgnd_F5">-0.5em;">,3C).-0.5em;-0.5em;">,3C).</span></span><span>3C</<a href="#R33" rid="R33" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401278">-0-0.5em<a href="#R43" rid="R43" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401298">-0-0.5em;">,3C).</span></span><span>3C</span></a>). Thirdly, nuclear TAp73 binding is displaced from TP53/p63 sites <a href="#R49" rid="R49" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401366">-0-0.5em;">,3C).</span></span><span>3C</span></a>). Thirdly, nuclear TAp73 binding <a href="#R34" rid="R34" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401321">-0-0.5em-0.5-0.5em;">,3C).</span></span><span>3C</span></a>). Thirdly, nuclear TAp7<a href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401320">--0.5em<a href="#R8" rid="R8" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401271">--0.5em<a href="#R48" rid="R48" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401361">p"p" id="__tag_569401361">48</a>) reveal a complex, genome-wide transcriptional regulatory mechanism whereby TP53, NF-κB and AP-1 family members interact to promote a broad signaling network favoring tumor survival and inflammation. Our current study helps explain the global mechanisms underlying the newly discovered deregulated TP53/p63 network and inflammation, presented recently by<a href="#R2" rid="R2" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401337">pp" id="__tag_569401361">48</a>) revea<a href="#R50" rid="R50" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401274">p"p" id="__tag_569401361">48</a>) reveal a complex, genome-wide transcriptional regulatory mechanism whereby TP53, NF-κB and AP-1 family members interact to promote a broad signaling network favoring tumor survival and inflammation. Our current study helps explain the global mechanip" ip" id=p" id="__tag_569401361">48</a>)p" id="__tag_569401361">48</a>) reveal a complex, genome-wide transcrp" idp" id="__tag_569401361">48</a>) reveal a p" id="__tag_569401361">48</a>) reveal a complex, p" idp" id="__tag_569401361">48</a>) reveal a complex, genome-wide transcriptional regulatory mechanism whereby TP53, NF-κB and AP-1 family members interact to promote a broad signaling network n GAIIx sequencer from Illumina following the manufacturer's protocol (San Diego, CA). Sequence reads were mapped to the UCSC human genome Hg18 assembly using the Eland algorithm (Illumina), permitting up to 2 mismatches and no gaps. Only unique mapped reads were used in the binding peak calling analysis. To identify binding peaks, we employed MACS (<a href="#R51" rid="R51" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401351">n n GAIIx sequencer from Illumina following the manufacturer's protocol (San Diego, CA). Sequence reads were mapped to the UCSC human genome Hg18 assembly using the Eland algorithm (Illumina), permitting up to 2 mismatches and no gaps. Only unique mapped reads were used in the binding peak calling analysis. To identify binding peaks, we employed MACS (<a href="#R51" rid="R51" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401351">51</a>), in which a dynamic Poisson distribution model was used to detect the statistically significant binding peaks in ChIP samples compared to DNA input controls. MA<a href="#R52" rid="R52" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401350">n n GAIIx sequencer from Illumina following the manufacturer's protocol (San Diego, CA). Sequence reads were mapped to the UCSC human genome Hg18 assembly using the Eland algorithm (Illumina), permitting up to 2 m<a href="#R53" rid="R53" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401260">n n GAIIx sequencer from Illumina following the manufacturer's protocol (San Diego, CA). Sequence reads we<a href="#R54" rid="R54" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401309">n n GAIIx sequencer from n GAIIx seqn GAIIx sequencer from Illumina following the manufacturer's proto<a href="#R55" rid="R55" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_569401291">n n GAIIx sequencer from Illumina following the manufacturer's protocol (San Diego, CA). Sequence reads were mapped to the UCSC human genome Hg18 assembly using the Eland algorithm (Illumina), permittitersection analysis were performed using customized python/R scripts. ChIP-seq experiments were repeated in UM-SCC46 cell lines, and a representative experiment was analyzed and presented in <a href="#SD12" rid="SD12" class=" supplementary-material">tersection analysis wtersection analysis were performed using customized python/R scripts. ChIP-seq experiments were repeated in UM-SCC46 cell lines, and a representative experiment was analyzed and presented in <a href="#SD12" rid="SD12" class=" supplementary-material">Supplemental<a href="http://biowulf.nih.gov" ref="reftype=extlink&article-id=5093089&issue-id=278503&journal-id=319&FROM=Article%7CBody&TO=External%7CLink%7CURI&rendering-type=normal" target="pmc_ext">ering-type=normal" tarering-erinering-ering-ering-type=normal" target="pmc<a id="supplementary-material-sec">erinering-type=normal" target="pmc_ext">http://biowulf.nih.gov</a>).</p><eringering-type=normal" targetering-type=normal" target="pmc_ext"ering-type=normal" target="peringering-type=normal" target="pmc_ext">http://biow<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Information.docx">ering-type=normal" erinering-type=normalering-ering-ering-ering-type=normal" target="pmc_ext"ering-type=normal" targeeringering-type=normal" target="pmc_ext">http://biow<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Table_1.tif">ering-type=normal" erinering-type=normaering-ering-ering-ering-type=normal" target="pmc_ext"ering-type=normal" targeeringering-type=normal" target="pmc_ext">http://biow<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Table_2.tif">ering-type=normal" erinering-type=normaering-ering-ering-ering-type=normal" target="pmc_ext"ering-type=normal" targeeringering-type=normal" target="pmc_ext">http://biow<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Table_3.tif">ering-type=normal" erinering-type=normaering-ering-ering-ering-type=normal" target="pmc_ext"ering-type=normal" targeteringering-type=normal" target="pmc_ext">http://biow<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Table_4a.xlsb">ering-type=normal" erinering-type=normaering-ering-ering-ering-type=normal" target="pmc_ext"ering-type=normal" targeteringering-type=normal" target="pmc_ext">http://biow<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Table_4b.xlsb">ering-type=normal" erinering-type=normaering-ering-ering-ering-type=normal" target="pmc_ext"ering-type=normal" targeeringering-type=normal" target="pmc_ext">http://biow<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Table_5.xlsx">ering-type=normal" erinering-type=normalering-ering-</div>iv><div class="sec suppmat" id="SD1iv><div class="sec suppmiv><div><div class="sec suppmat" id="SD18"><h4>Suppl<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Table_6.tif">iv><div class="sec iv><iv><div class="siv><diiv><diiv><diiv><div class="sec suppmat" id="SDiv><div class="sec suppmaiv><div><div class="sec suppmat" id="SD18"><h4>Suppl<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Figure_1.tif">iv><div class="sec iv><iv><div class="siv><diiv><diiv><diiv><div class="sec suppmat" id="SDiv><div class="sec suppmaiv><div><div class="sec suppmat" id="SD18"><h4>Suppl<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Figure_2.tif">iv><div class="sec iv><iv><div class="siv><diiv><diiv><diiv><div class="sec suppmat" id="SDiv><div class="sec suppmaiv><div><div class="sec suppmat" id="SD18"><h4>Suppl<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Figure_3.tif">iv><div class="sec iv><iv><div class="siv><diiv><diiv><diiv><div class="sec suppmat" id="SDiv><div class="sec suppmaiv><div><div class="sec suppmat" id="SD18"><h4>Suppl<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Figure_4.tif">iv><div class="sec iv><iv><div class="siv><diiv><diiv><diiv><div class="sec suppmat" id="SDiv><div class="sec suppmaiv><div><div class="sec suppmat" id="SD18"><h4>Suppl<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Figure_5.tif">iv><div class="sec iv><iv><div class="siv><diiv><diiv><diiv><div class="sec suppmat" id="SDiv><div class="sec suppmaiv><div><div class="sec suppmat" id="SD18"><h4>Suppl<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Figure_6.tif">iv><div class="sec iv><iv><div class="siv><diiv><diiv><diiv><div class="sec suppmat" id="SDiv><div class="sec suppmaiv><div><div class="sec suppmat" id="SD18"><h4>Suppl<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Figure_7.tif">iv><div class="sec iv><iv><div class="siv><diiv><di</div>v><div class="sec suppmat" id="SD9v><div class="sec suppmatv><div><div class="sec suppmat" id="SD9"><h4>Supplem<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Figure_8.tif">v><div class="sec sv><dv><div class="sv><divv><divv><divv><div class="sec suppmat" id="SD9"v><div class="sec suppmatv><div><div class="sec suppmat" id="SD9"><h4>Supplem<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Figure_9.tif">v><div class="sec sv><dv><div class="sev><divv><divv><divv><div class="sec suppmat" id="SD9v><div class="sec suppmat"v><div><div class="sec suppmat" id="SD9"><h4>Supplem<a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Figure_10.tif">v><div class="sec sv><dv><div class="sev><divv><divv><divv><divv><div class="sec suppmat" id="v><div class="sec suppmat" id="SD9"><h4>Supplemental Figure 8</v><div><div class="secv><div class="sec suppmat" id="SD9"><h4>Supplemental Figure 8</h4><div class="sup-box half_rhythm" id="d37e1424"><a href="/pmc/articles/PMC5093089/bin/NIHMS753191-supplement-Supplemental_Figure_8.tif">Click here to view.</a><sup>(15M, tif)</supnology, Alexandria, Virginia), and Mr. Eric Nicolson (Ithaca High School, Ithaca, New York NY) for their technical assistance and suggestions. The authors express appreciation to Drs. James W. Rocco and Leif W. Ellisen (Harvard University) for providing ΔNp63 and TAp63 expression vectors, Dr. Thomas Gilmore (Boston University) for cRel expression plasmids, Professor Gerry Melino (University of Leicester) for TAp73α expression plasmids, Dr. J. Silvio Gutkind (NIDCR/NIH) for IL-6 promoter reporter plasmids, Dr. Gourisankar Ghosh (UCSD) for the cRel expression plasmid, and Drs. Michal Karin (University of California, San Diego), Cheng-Ming Chiang (University of Texas, Southwestern) and Xuan Liu (University of California, Riverside) for critique of and helpful suggestions for the manuscript.nolonology, Alexandria, Virginia), and Mr. Eric Nicolson (Ithaca High School, Ithaca, New York NY) for their technical assistance and suggestions. The authors express appreciation to Drs. James W. Rocco and Leif W. Ellisen (Harvard University) for providing ΔNp63 and TAp63 expression vectors, Dr. Thomas Gilmore (Bostonolonologynologynology, Alexandria, Virginia), and Mr. Eric Nicolson (Itnology, Alexandria, Virginia), and Mr. Eric Nicolson (Ithaca High School, Ithaca, nolognology, Alexandria, nology, Alexandria, Virginia), and Mr.nology, Alexandria, Virgininology, Alexandria, Virginia), and Mr. Eric Nicolson (nolonology, Alexandria, Virginia), and Mr. Eric Nicolson (Ithaca High School, Ithaca, New York NY) for their technical assistance and suggestions. The authors express appreciation to Drs. James W. Rocco and Leif W. Ellisen (Harvard University) for providing ΔNp63 and TAp63 expression vectors, Dr. Thomas Gilmore (Boston University) for cRel expression plasmids, Professor Gerry Melino (University of Leicester) for TAp73α expression plasmids, Dr. J. Silvio Gutkind (NIDCR/NIH) for IL-6 promoter reporter plasmids, Dr. Gourisankar Ghosh (UCSD) for the nolonolonologynologynology, Alexandria, Vm140671114615200" class="tsec sec">m140671114615200" class="tsec sec"><h2 class="head no_bottom_margin" id="__ref-listm1406m140671114615200" class="tsec sec"><h2 class="headm140671114615200" class="tsec sec"><h2 class="hem140671114615200" class="tsec sec"><h2 class="head no_bottom_margin" id="__ref-listidm140671114615200title">References</h2><div class="rm14067m140671114615200" class="tsec sec"m14067111461m140671114615200" class="m140671114615200" clam1406711m140671114615200" class="tsec <a class="int-reflink" href="/pmc/articles/PMC4311405/">m140671114615200m1406m14067111m140671114615200" class="tsec sec<a href="/pubmed/25631445" target="pmc_ext" ref="reftype=pubmed&article-id=5093089&issue-id=278503&journal-id=319&FROM=Article%7CCitationRef&TO=Entrez%7CPubMed%7CRecord&rendering-type=normal">m14067m1406m140671m140671m14067m140671114615200" class="tsec sec"><h2 class="he<span class="element-citation">Hoadley KA, Yau C, Wolf DM, Cherniack AD, Tamborero D, Ng S, et al. 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and neck squamous cell carcinoma. <span><span class="ref-journal">Cancer Res. </span>2001;<span class="ref-vol">61</span>(15):5911?8.</span> <span class="nowrap ref pubmed">[<a href="/pubmed/11479233" targetnterlenterleukin-8 and vascular endothelianterleukin-8nterleukin-8 and vasculanterleukin-8 and vascnterleukinterleukin-8 and vascular endothe<a href="/pubmed/15221009" target="pmc_ext" ref="reftype=pubmed&article-id=5093089&issue-id=278503&journal-id=319&FROM=Article%7CCitationRef&TO=Entrez%7CPubMed%7CRecord&rendering-type=normal">nterlenterlnterleunterleunterlenterleukin-8 and vascular endothelial growth factonterleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. <nterlenterleukin-8 and vascular endothelial growth facnterleukin-8nterleukin-8 and vasculnterleukin-8 and vanterleukinterleukin-8 and vascular endothe<a href="/pubmed/17896954" target="pmc_ext" ref="reftype=pubmed&article-id=5093089&issue-id=278503&journal-id=319&FROM=Article%7CCitationRef&TO=Entrez%7CPubMed%7CRecord&rendering-type=normal">nterlenterlnterleunterleunterlenterleukin-8 and vascular endothelial growth factonterleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. <span><span class="ref-journal">Cancer Res. </span>2001;<span class="ref-vol">61</span>(nterlenterleukin-8 and vascular endothelnterleukin-8nterleukin-8 and vascularnterleuki031):396?400.031):396?031):396?400.</span> <span class<a href="/pubmed/15772665" target="pmc_ext" ref="reftype=pubmed&article-id=5093089&issue-id=278503&journal-id=319&FROM=Article%7CCitationRef&TO=Entrez%7CPubMed%7CRecord&rendering-type=normal">031):3031):031):39031):39031):3031):396?400.</span> <span class="nowrap ref pubm031):396?400.</span> <span class="nowrap ref pubmed">[<a href="/pubmed/15772665" target="pmc_ext" 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