p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage

Zhi-Min Yuan, Hisashi Shioya, Takatoshi Ishiko, Xiangao Sun, Jijie Gu, YinYin Huang, Hua Lu, Surender Kharbanda, Ralph Weichselbaum and Donald Kufe ()
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Zhi-Min Yuan: Harvard School of Public Health
Hisashi Shioya: Dana-Farber Cancer Institute, Harvard Medical School
Takatoshi Ishiko: Dana-Farber Cancer Institute, Harvard Medical School
Xiangao Sun: Dana-Farber Cancer Institute, Harvard Medical School
Jijie Gu: Harvard School of Public Health
YinYin Huang: Dana-Farber Cancer Institute, Harvard Medical School
Hua Lu: Oregon Health Science University
Surender Kharbanda: Dana-Farber Cancer Institute, Harvard Medical School
Ralph Weichselbaum: University of Chicago
Donald Kufe: Harvard School of Public Health

Nature, 1999, vol. 399, issue 6738, 814-817

Abstract: Abstract The protein p73 is a structural and functional homologue of the p53 tumour-suppressor protein but, unlike p53, it is not induced in response to DNA damage1,2. The tyrosine kinase c-Abl is activated by certain DNA-damaging agents3 and contributes tothe induction of programmed cell death (apoptosis) by p53-dependent and p53-independent mechanisms4. Here we show that c-Abl binds to p73 in cells, interacting through its SH3 domain with the carboxy-terminal homo-oligomerization domain of p73. c-Abl phosphorylates p73 on a tyrosine residue at position 99 both in vitro and in cells that have been exposed to ionizing radiation. Our results show that c-Abl stimulates p73-mediated transactivation and apoptosis. This regulation of p73 by c-Abl in response to DNA damage is also demonstrated by a failure of ionizing-radiation-induced apoptosis after disruption of the c-Abl–p73 interaction. These findings show that p73 is regulated by a c-Abl-dependent mechanism and that p73 participates in the apoptotic response to DNA damage.

Date: 1999
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DOI: 10.1038/21704

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