Journal
CELL DEATH AND DIFFERENTIATION
Volume 12, Issue 12, Pages 1564-1577Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4401774
Keywords
apoptosis; CD95; chemosensitivity; hepatocellular carcinoma; dominant-negative p73; TAp73
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We investigated the mechanisms by which TAp73 beta and dominant-negative p73 (Delta Np73) regulate apoptosis. TAp73 beta transactivated the CD95 gene via the p53-binding site in the first intron. In addition, TAp73 beta induced expression of proapoptotic Bcl-2 family members and led to apoptosis via the mitochondrial pathway. Endogenous TAp73 was upregulated in response to DNA damage by chemotherapeutic drugs. On the contrary, Delta Np73 conferred resistance to chemotherapy. Inhibition of CD95 gene transactivation was one mechanism by which Delta Np73 functionally inactivated the tumor suppressor action of p53 and TAp73 beta. Concomitantly, Delta Np73 inhibited apoptosis emanating from mitochondria. Thus, Delta Np73 expression in tumors selects against both the death receptor and the mitochondrial apoptosis activity of TAp73 beta. The importance of these data is evidenced by our finding that upregulation of Delta Np73 in hepatocellular carcinoma patients correlates with reduced survival. Our data indicate that Delta Np73 is an important gene in hepatocarcinogenesis and a relevant prognostic factor.
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