Interference with the p53 family network contributes to the gain of oncogenic function of mutant p53 in hepatocellular carcinoma

Abstract

Whereas the hallmark of wild-type p53 is its tumor suppressor activity, tumor-associated mutant p53 proteins can exert novel anti-apoptotic gain-of-function activities, which confer a selective advantage upon tumor cells harboring such mutations. We investigated the molecular mechanisms of mutant p53 gain-of-function in hepatocellular carcinoma with special emphasis on the interaction of mutant p53 gain-of-function proteins with the p53 family members p63 and p73. Mutant forms of p53, namely the hot-spot mutants p53R143A, p53R175D, p53R175H, p53R248W, and p53R273H, acquire anti-apoptotic gain-of-function in hepatocellular carcinoma by repressing the activity of genes regulating both, the extrinsic apoptosis pathway initiated by ligation of death receptors and the intrinsic/mitochondrial apoptosis pathway. In the presence of mutated p53, the CD95L-CD95 apoptotic pathway is markedly attenuated. This is due to repression of CD95 gene transcription by mutant p53. In addition, these mutants repress the expression of the Bax gene and attenuate mitochondria-mediated apoptosis signaling. Furthermore, and of clinical relevance, these gain-of-function mutants are anti-apoptotic due to their inhibitory interaction with the pro-apoptotic p53 family members TAp63 and TAp73. p53 gain-of-function mutants significantly decrease activation of pro-apoptotic target genes by wild-type p53, TAp63, and TAp73. This contributes to the ability of cancer cells to withstand DNA damage-induced apoptosis. Interference with the interaction of p53 gain-of-function mutants with TAp63 or TAp73 may thus sensitize hepatocellular carcinoma to elimination by therapy.