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 splicing, can also induce apoptosis. 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.

Gong, J., Costanzo, A., Yang, H.q., Melino, G., Kaelin, J., Levrero, M., et al. (1999). The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. NATURE, 399(6738), 806-809 [10.1038/21690].

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

COSTANZO, ANTONIO;MELINO, GENNARO;
1999-01-01

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 splicing, can also induce apoptosis. 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.
1999
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/35 - MALATTIE CUTANEE E VENEREE
English
Con Impact Factor ISI
cisplatin; DNA; oncoprotein; protein p53; protein tyrosine kinase; animal cell; apoptosis; article; cancer cell; controlled study; cytotoxicity; DNA damage; embryo; enzyme activity; enzyme regulation; gene; half life time; human; human cell; immunoblotting; mouse; nonhuman; priority journal; 3T3 Cells; Animals; Apoptosis; Base Pair Mismatch; Cisplatin; DNA; DNA Damage; DNA Repair; DNA-Binding Proteins; Genes, Tumor Suppressor; Humans; Mice; Nuclear Proteins; Proto-Oncogene Proteins c-abl; Tumor Cells, Cultured; Tumor Suppressor Proteins; Animalia
Gong, J., Costanzo, A., Yang, H.q., Melino, G., Kaelin, J., Levrero, M., et al. (1999). The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. NATURE, 399(6738), 806-809 [10.1038/21690].
Gong, J; Costanzo, A; Yang, Hq; Melino, G; Kaelin, Jrwg; Levrero, M; Wang, Jyj
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/51962
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