8626

TP63

AIS|B(p51A)|B(p51B)|EEC3|KET|LMS|NBP|OFC8|RHS|SHFM4|TP53CP|TP53L|TP73L|p40|p51|p53CP|p63|p73H|p73L;tumor protein p63;TP63;tumor protein p63

CUSP|amplified in squamous cell carcinoma|chronic ulcerative stomatitis protein|keratinocyte transcription factor KET|transformation-related protein 63|tumor protein 63|tumor protein p53-competing protein|tumor protein p63 deltaN isoform delta

3q28

protein-coding

Inflammation-induced activation of proto-oncogenic NF-kappaB/REL and dysfunction of tumor suppressor TP53/p63/p73 family transcription factors are key events in cancer progression. How inflammatory signaling coordinates dysregulation of these two transcription factor families during oncogenesis remains incompletely understood. Here, we observed that oncoprotein c-REL and tumor suppressor TAp73 are coexpressed and complex with DeltaNp63alpha in the nucleus of a subset of head and neck squamous cell carcinoma (HNSCC) cell lines with mutant (mt)TP53. TNF-alpha, a proinflammatory cytokine, promoted c-REL nuclear translocation, c-REL/DeltaNp63alpha interaction, and dissociation of TAp73 from DeltaNp63alpha and the nucleus to the cytoplasm, whereas c-REL siRNA knockdown attenuated this effect. Overexpression of c-REL or a c-REL kappaB-site DNA-binding mutant enhanced protein interaction with DeltaNp63alpha and TAp73 dissociation, implicating c-REL/DeltaNp63alpha-specific interactions in these effects. We discovered that TNF-alpha or genetic alteration of c-REL expression inversely modulates DeltaNp63alpha/TAp73 interactions on distinct p63 DNA-binding sites, including those for key growth arrest and apoptotic genes p21WAF1, NOXA, and PUMA. Functionally, c-REL repressed these genes and the antiproliferative effects of TNF-alpha or TAp73. Conversely, c-REL siRNA depletion enhanced TAp73 promoter interaction and expression of genes mediating growth arrest and apoptosis. Similar to TNF-alpha-treated HNSCC lines, human HNSCC tumors and hyperplastic squamous epithelia of transgenic mice overexpressing DeltaNp63alpha that exhibit inflammation also show increased nuclear c-REL/DeltaNp63alpha and cytoplasmic TAp73 localization. These findings unveil a novel and reversible dynamic mechanism whereby proinflammatory cytokine TNF-alpha-induced c-REL/DeltaNp63alpha interactions inactivate tumor suppressor TAp73 function, promoting TNF-alpha resistance and cell survival in cancers with mtTP53.

Fanconi anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras-oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population.