The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage

JianGen Gong, Antonio Costanzo, Hong-Qiong Yang, Gerry Melino, William G. Kaelin, Massimo Levrero and Jean Y. J. Wang ()
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JianGen Gong: University of California
Antonio Costanzo: Laboratory of Gene Expression, Fondazione A Cesalpino, University of Rome La Sapienza
Hong-Qiong Yang: University of California
Gerry Melino: Biochemistry Laboratory, Istituto Dermopatico dell'Immacolata-IRCCS, University of Rome Tor Vergata 00133
William G. Kaelin: Howard Hughes Medical Institute, and Dana Farber Cancer Institute
Massimo Levrero: Laboratory of Gene Expression, Fondazione A Cesalpino, University of Rome La Sapienza
Jean Y. J. Wang: University of California

Nature, 1999, vol. 399, issue 6738, 806-809

Abstract: Abstract Cancer chemotherapeutic agents such as cisplatin exert their cytotoxic effect by inducing DNA damage and activating programmed cell death (apoptosis). The tumour-suppressor protein p53 is an important activator of apoptosis. Although p53-deficient cancer cells are less responsive to chemotherapy, their resistance is not complete, which suggests that other apoptotic pathways may exist. A p53 -related gene, p73, which encodes several proteins as a result of alternative splicing1,2, can also induce apoptosis3. Here we show that the amount of p73 protein in the cell is increased by cisplatin. This induction of p73 is not seen in cells unable to carry out mismatch repair and in which the nuclear enzyme c-Abl tyrosine kinase is not activated by cisplatin. The half-life of p73 is prolonged by cisplatin and by co-expression with c-Abl tyrosine kinase; the apoptosis-inducing function of p73 is also enhanced by the c-Abl kinase. Mouse embryo fibroblasts deficient in mismatch repair or in c-Abl do not upregulate p73 and are more resistant to killing by cisplatin. Our results indicate that c-Abl and p73 are components of a mismatch-repair-dependent apoptosis pathway which contributes to cisplatin-induced cytotoxicity.

Date: 1999
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DOI: 10.1038/21690

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