No abstract

A human p53 homologue, p63 (p40͞p51͞p73L͞CUSP) that maps to the chromosomal region 3q27-29 was found to produce a variety of transcripts that encode DNA-binding proteins with and without a trans-activation domain (TA-or ⌬N-, respectively). The p63 gene locus was found to be amplified in squamous cell carcinoma, and overexpression of ⌬Np63 (p40) led to increased growth of transformed cells in vitro and in vivo. Moreover, p63-null mice displayed abnormal epithelial development and germ-line human mutations were found to cause ectodermal dysplasia. We now demonstrate that certain p63 isotypes form complexes with p53. p53 mutations R175H or R248W abolish the association of p53 with p63, whereas V143A or R273H has no effect. Deletion studies suggest that the DNA-binding domains of both p53 and p63 mediate the association. Overexpression of wild type but not mutant (R175H) p53 results in the caspase-dependent degradation of certain ⌬Np63 proteins (p40 and ⌬Np63␣). The association between p53 and ⌬Np63 supports a previously unrecognized role for p53 in regulation of ⌬Np63 stability. The ability of p53 to mediate ⌬Np63 degradation may balance the capacity of ⌬Np63 to accelerate tumorigenesis or to induce epithelial proliferation.

We have identified a new human p53 homologue, p40 (p51/p63). This gene was mapped to the distal arm of 3q and was found to be essential for normal epithelial development. We used microsatellite and FISH analyses to search for genetic alterations of p40 in primary HNSCC. A more precise localization of p40 was completed using 6 known markers on 3q and a newly isolated microsatellite marker within the p40 gene. We also determined the genomic organization of the p40 gene using human YAC and BAC clones. Microsatellite analysis revealed that 14 of 26 (54%) primary HNSCC had allelic imbalance in at least 1 of the 7 microsatellite loci. However, FISH analysis with a p40 probe showed that a majority of HNSCC had an increased copy number of the locus regardless of allelic status. Thus, overrepresentation of the p40 locus may play an important role in the development of HNSCC. Int. J. Cancer 86:684–689, 2000. © 2000 Wiley‐Liss, Inc.