The p53-related genes, p51/p63 and p73, have been isolated respectively from cDNA libraries of skeletal muscle and the brain, and their structural features and biological functions have been compared. High expression of p51A (TAp63gamma) in the skeletal muscle tissue drove us to investigate a differentiation-inducible myoblastic cell line which showed increased p51A expression after differentiation induction. Tissue-specific expression was further confirmed by reverse transcriptase-polymerase chain reaction (RT - PCR) using primers specific for DeltaN (TA-domain lacking p51), p51A, and p51B expression. p51A alone induced erythrodifferentiation when expressed in the erythroleukemia line (Tg-gp55-1-2-3) expressing a temperature-sensitive mutant of p53, and induced remarkable apoptosis when wild-type p53 expression was induced by the temperature shift to 32 degrees C. Human p51A and p53 were introduced exogenously into the above erythroleukemia cells, and although their expression was rather low, both p51A and p53 proteins were induced by DNA-damaging treatment with UV and ActinomycinD. However, the protein-protein interactions analyzed by a yeast two-hybrid assay between p51 and p53, between p51 and p73, and between p51 and oncoproteins showed that p51 is functionally rather distant from p53. Extensive mutation analysis of p51/p63 in human tumors revealed only four mutations in 80 non-small cell lung carcinomas; two adenocarcinoma cases possessing Glu31His mutations in the transactivation domain (TA) domain, suggesting that p51/p63 is not a Knudson type tumor suppressor gene. Mutation and loss of heterozygosity (LOH) of p73, deregulated expression of p73 and loss of imprinting of p73 are also discussed.