p63 and p73: Life and Death in Squamous Cell Carcinoma

The p53 family member p63 plays an essential role in the developing epithelium, and overexpression of the ΔNp63a isoform is frequently observed in human squamous cell carcinomas (SCCs). These findings have suggested that ΔNp63a might function as an oncogene within squamous epithelial cells. Nevertheless, the mechanism by which ΔNp63a might promote tumorigenesis remains poorly understood, and data from mouse models implies that the p63 locus might in fact function as a tumor suppressor in these same tissues. A recent study using RNA interference in human SCC-derived cell lines shows that ΔNp63a mediates an essential survival function in human SCC cells by virtue of its ability to suppress the pro-apoptotic function of the related p53 family member p73. These findings support an oncogenic role for ΔNp63a and they demonstrate the existence of critical physical and functional interactions between endogenous p53 family members in human cancer. Specific chemotherapeutic agents and future targeted approaches may be able to exploit this pathway to therapeutic advantage.

[1]  Rebecca A. Ihrie,et al.  Perp Is a p63-Regulated Gene Essential for Epithelial Integrity , 2005, Cell.

[2]  M. Osada,et al.  p51/p63 Controls Subunit α3 of the Major Epidermis Integrin Anchoring the Stem Cells to the Niche* , 2004, Journal of Biological Chemistry.

[3]  S. Lowe,et al.  p63 deficiency activates a program of cellular senescence and leads to accelerated aging. , 2005, Genes & development.

[4]  S. Knuutila,et al.  DNA gains in 3q occur frequently in squamous cell carcinoma of the lung, but not in adenocarcinoma , 1998, Genes, chromosomes & cancer.

[5]  A. Yang,et al.  REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. , 2002, Molecular cell.

[6]  R. Poon,et al.  How Many Mutant p53 Molecules Are Needed To Inactivate a Tetramer? , 2004, Molecular and Cellular Biology.

[7]  X. Chen,et al.  The common and distinct target genes of the p53 family transcription factors , 2004, Cellular and Molecular Life Sciences CMLS.

[8]  T. Davison,et al.  p73 and p63 Are Homotetramers Capable of Weak Heterotypic Interactions with Each Other but Not with p53* , 1999, The Journal of Biological Chemistry.

[9]  A. Yang,et al.  On the shoulders of giants: p63, p73 and the rise of p53. , 2002, Trends in genetics : TIG.

[10]  A. Mills.  p63: oncogene or tumor suppressor? , 2006, Current opinion in genetics & development.

[11]  Yusuke Nakamura,et al.  The p53 Family Member Genes Are Involved in the Notch Signal Pathway* , 2002, The Journal of Biological Chemistry.

[12]  B. Gusterson,et al.  p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. , 2003, Cancer cell.

[13]  C. Prives,et al.  A Subset of Tumor-Derived Mutant Forms of p53 Down-Regulate p63 and p73 through a Direct Interaction with the p53 Core Domain , 2001, Molecular and Cellular Biology.

[14]  H. Vogel,et al.  p63 is a p53 homologue required for limb and epidermal morphogenesis , 1999, Nature.

[15]  A. Yang,et al.  p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. , 1998, Molecular cell.

[16]  A. Yang,et al.  p63 and p73: p53 mimics, menaces and more , 2000, Nature Reviews Molecular Cell Biology.

[17]  M. Irwin.  Family Feud in Chemosensitvity: p73 and Mutant p53 , 2004, Cell cycle.

[18]  U. Moll,et al.  p63 and p73: roles in development and tumor formation. , 2004, Molecular cancer research : MCR.

[19]  Ming-Rong Wang,et al.  Elevated expression of p63 protein in human esophageal squamous cell carcinomas , 2002, International journal of cancer.

[20]  A. Yang,et al.  Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. , 2005, Cancer cell.

[21]  R. Liang,et al.  Hypermethylation of gene promoters in hematological neoplasia , 2002, Hematological oncology.

[22]  J. Jen,et al.  AIS is an oncogene amplified in squamous cell carcinoma. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Y. Matsumura,et al.  TAp63γ (p51A) and dNp63α (p73L), two major isoforms of the p63 gene, exert opposite effects on the vascular endothelial growth factor (VEGF) gene expression , 2002, Oncogene.

[24]  D. Billheimer,et al.  IGFBP-3 is a direct target of transcriptional regulation by DeltaNp63alpha in squamous epithelium. , 2005, Cancer research.

[25]  D. Sidransky,et al.  DeltaNp63alpha levels correlate with clinical tumor response to cisplatin. , 2005, Cell cycle.

[26]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[27]  F. Bootz,et al.  Expression of p53 and its homologues in primary and recurrent squamous cell carcinomas of the head and neck , 2002, International journal of cancer.

[28]  Christopher P. Crum,et al.  p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development , 1999, Nature.

[29]  S. Nomoto,et al.  DeltaNp63 induces beta-catenin nuclear accumulation and signaling. , 2002, Cancer cell.

[30]  W. Hahn,et al.  Chemosensitivity linked to p73 function. , 2003, Cancer cell.

[31]  J. Pietenpol,et al.  Dominant Negative p63 Isoform Expression in Head and Neck Squamous Cell Carcinoma , 2004, The Laryngoscope.

[32]  L. Ellisen,et al.  p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. , 2006, Cancer cell.

[33]  P. Hainaut,et al.  WITHDRAWN: Expression of p53, p63, and p73 isoforms in squamous cell carcinoma and adenocarcinoma of esophagus☆,☆☆ , 2005, Biochemical and Biophysical Research Communications - BBRC.

[34]  A. Yang,et al.  Down-regulation of p63 is required for epidermal UV-B-induced apoptosis. , 2000, Cancer research.

[35]  J. Pietenpol,et al.  Ultraviolet radiation induces phosphorylation and ubiquitin-mediated degradation of DeltaNp63alpha. , 2005, Cell cycle.

[36]  G. Melino,et al.  TAp63α induces apoptosis by activating signaling via death receptors and mitochondria , 2005, The EMBO journal.

[37]  A. Mills,et al.  p63: A New Link Between Senescence and Aging , 2006, Cell cycle.

[38]  Zhongmin Guo,et al.  RACK1 and stratifin target DeltaNp63alpha for a proteasome degradation in head and neck squamous cell carcinoma cells upon DNA damage. , 2004, Cell cycle.

[39]  Tim Crook,et al.  Functional regulation of p73 and p63: development and cancer. , 2003, Trends in biochemical sciences.

[40]  K. Tsai,et al.  p63 and p73 are required for p53-dependent apoptosis in response to DNA damage , 2002, Nature.

[41]  Yu Shyr,et al.  Significance of p63 amplification and overexpression in lung cancer development and prognosis. , 2003, Cancer research.

[42]  R. Knight,et al.  p63 and p73 transactivate differentiation gene promoters in human keratinocytes. , 2000, Biochemical and biophysical research communications.

[43]  B. Trink,et al.  p63 and p73: teammates or adversaries? , 2006, Cancer cell.

[44]  K. Vousden,et al.  Minireviewp 53 : Death Star able to induce the defensive p 53 response to oncogene , 2000 .

[45]  P. Pandolfi,et al.  Regulation of the p73 protein stability and degradation. , 2005, Biochemical and biophysical research communications.

[46]  E. Sturgis,et al.  Differential expression of p53 gene family members p63 and p73 in head and neck squamous tumorigenesis. , 2002, Human pathology.

[47]  A. Yang,et al.  p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours , 2000, Nature.