Frequent alteration of p63 expression in human primary bladder carcinomas

p63, a recently identified member of the p53 gene family, encodes multiple products with transactivating, death-inducing, and dominant-negative activi ties. To explore the penetrance of p63 in bladder carcinogenesis, we perfor med expression and mutation analyses of two major Isotypes, TAp63 and Delta Np63, in 63 bladder specimens. In 12 normal tissues, TAp63 was expressed a t an easily detectable level whereas Delta Np63 was absent or extremely low . While none of 47 carcinomas showed allelic deletion of the gene, marked r eduction of TAp63 and abnormal overexpression of Delta Np63 were found in 2 5 (53.2%) and 30 (63.8%) carcinomas, respectively. Tumor-specific alteratio n of TAp63 and Delta Np63 expression was identified in two and three of six matched sets, respectively. In addition, reduced expression of TAp63 showe d a correlation with tumor stage and grade. Abnormal expression of TAp63 or Delta Np63 isoform was also observed in three of four cell lines, and trea tment with 5-Aza-2'-deoxycytidine led to up- or down-regulation of TAp63 an d/or Delta Np63 expression, suggesting that the promoters of both isoforms might be affected by DNA methylation, but not in a reciprocal fashion. No s equence alteration of p63 was identified in 47 carcinomas whereas 17 (34.8% ) of these showed p53 mutations, and no association between p63 expression and the mutational status of p53 or expression of p21(Waf1), MDM2, and 14-3 -3 sigma was recognized. Our data suggest that altered expression of p63 is a frequent event in bladder carcinogenesis and might contribute to the pro gression of bladder tumors, possibly via the mechanism(s) distinct from the p53 pathway.