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

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.

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Figure 1: Induction of p73 by cisplatin (CDDP) correlated with activation of c-Abl tyrosine kinase and increased cell death.
Figure 2: Stabilization of p73 protein by cisplatin and by c-Abl tyrosine kinase.
Figure 3: c-Abl enhances the apoptosis function of p73, but not p53.
Figure 4: Differential induction of p53 and p73 by cisplatin in mouse embryo fibroblasts with defined mutations.
Figure 5: Defective cellular MLH1, c-Abl or p73 reduces the sensitivity to cisplatin.

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Acknowledgements

We thank I. Hunton for the preparation of p53- and c-Abl-deficient MEFs, R.Kucherlapati and R. Kolodner for the MLH1-deficient MEFs, and R. Kolodner for critically reading the manuscript. This work was supported by grants from AIRC and CNR-PF Biotechnologie (to M.L.) and from the NIH (to J.Y.J.W.).

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Correspondence to Jean Y. J. Wang.

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Gong, J., Costanzo, A., Yang, HQ. et al. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399, 806–809 (1999). https://doi.org/10.1038/21690

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