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Molecular and Cellular Biology, September 2001, p. 5869-5878, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.5869-5878.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

c-Abl Regulates p53 Levels under Normal and Stress Conditions by Preventing Its Nuclear Export and Ubiquitination

Ronit Vogt Sionov,1 Sabrina Coen,1 Zehavit Goldberg,1 Michael Berger,1 Beatrice Bercovich,2 Yinon Ben-Neriah,1 Aaron Ciechanover,2 and Ygal Haupt1,*

Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem 91120,1 and Department of Biochemistry, The Rappaport Family Institute for Research in the Medical Sciences and the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096,2 Israel

Received 8 March 2001/Returned for modification 11 May 2001/Accepted 4 June 2001

The p53 protein is subject to Mdm2-mediated degradation by the ubiquitin-proteasome pathway. This degradation requires interaction between p53 and Mdm2 and the subsequent ubiquitination and nuclear export of p53. Exposure of cells to DNA damage results in the stabilization of the p53 protein in the nucleus. However, the underlying mechanism of this effect is poorly defined. Here we demonstrate a key role for c-Abl in the nuclear accumulation of endogenous p53 in cells exposed to DNA damage. This effect of c-Abl is achieved by preventing the ubiquitination and nuclear export of p53 by Mdm2, or by human papillomavirus E6. c-Abl null cells fail to accumulate p53 efficiently following DNA damage. Reconstitution of these cells with physiological levels of c-Abl is sufficient to promote the normal response of p53 to DNA damage via nuclear retention. Our results help to explain how p53 is accumulated in the nucleus in response to DNA damage.

* Corresponding author. Mailing address: Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem 91120, Israel. Phone: 972-2-6757103. Fax: 972-2-6424653. E-mail: haupt{at}md.huji.ac.il.

Molecular and Cellular Biology, September 2001, p. 5869-5878, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.5869-5878.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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