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Development-223

DNA-56

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Endocrine-66

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Extracellular Matrix-30

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Gene Expression-178

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Heart-61

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Chapter category: Oncogenes

TP63, TP73: The Guardian’s Elder Brothers

Chapter authors:
Stephanie Courtois, Pierre Hainaut and Claude Caron de Fromentel

TP73 and TP63 recently emerged as sharing overall architectural similarities with TP53. Phylogeny indicates that these three genes derive from a common ancestor, thus defining a new gene family. All three genes bind similar DNA consensus sequences in the promoters of many genes and regulate common generic aspects of growth control, survival, DNA repair or differentiation. However, their regulation patterns are distinct. While p53 is an ubiquitous, stress-response protein regulated at the post-translational level, p63 and p73 are expressed in a tissue and differentiation-specific manner and are also regulated at the transcriptional level. This regulation results in isoforms generated by alternative splicing or by the use of different promoters. They differ from each other in their C-terminus (which contains important regulatory domains) and, most strikingly, in their N-terminus. Thus, the major forms of p63 and p73 in many normal tissues are ∆N isoforms, which lack the transactivation domain, and can behave as repressors of the genes normally regulated by transactivation-competent (TA) forms of the protein. Control of the balance between levels of TA and ∆N forms of p63 and p73 is important in differentiation. Mice lacking TP63 or TP73 are not predisposed to cancer, but show developmental defects. In particular, TP63 knock-out mice have major defects in cranial and limb morphogenesis, and in the formation of squamous epithelia. These defects are partially recapitulated in human subjects with germline mutation in TP63. There is growing evidence that p63 and p73 are involved in carcinogenesis through several mechanisms. For instance, amplification of TP63 in squamous cancers results in overexpression of a ∆N protein that may counteract suppression by p63 as well as other family members. On the other hand, some mutant p53 can bind and inactivate p63 or p73, providing a mechanism for mutant p53 “gain-of-function” effect.

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