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TAp73/DNp73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma

M Muller, T Schilling, AE Sayan, A Kairat, K Lorenz, H Schulze-Bergkamen, M Oren, A Koch, A Tannapfel, W Stremmel, G Melino and PH Krammer


Cell Death and Differentiation (2005) 12, 1564–1577


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We investigated the mechanisms by which TAp73b and dominant-negative p73 (DNp73) regulate apoptosis. TAp73b transactivated the CD95 gene via the p53-binding site in the first intron. In addition, TAp73b induced expression of proapoptotic Bcl-2 familymembers and led to apoptosis via themitochondrial pathway. Endogenous TAp73 was upregulated in response to DNA damage by chemotherapeutic drugs. On the contrary, DNp73 conferred resistance to chemotherapy. Inhibition of CD95 gene transactivation was one mechanism by which DNp73 functionally inactivated the tumor suppressor action of p53 and TAp73b. Concomitantly, DNp73 inhibited apoptosis emanating from mitochondria. Thus, DNp73 expression in tumors selects against both the death receptor and the mitochondrial apoptosis activity of TAp73b. The importance of these data is evidenced by our finding that upregulation of DNp73 in hepatocellular carcinoma patients correlates with reduced survival. Our data indicate that DNp73 is an important gene in hepatocarcinogenesis and a relevant prognostic factor.


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