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Molecular and Cellular Biology, May 2002, p. 3292-3300, Vol. 22, No. 10
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.10.3292-3300.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

c-Abl Tyrosine Kinase Regulates the Human Rad9 Checkpoint Protein in Response to DNA Damage

Kiyotsugu Yoshida,1 Kiyoshi Komatsu,2 Hong-Gang Wang,2 and Donald Kufe1*

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115,1 Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, Florida 336122

Received 19 November 2001/ Returned for modification 8 January 2002/ Accepted 12 February 2002

The ubiquitously expressed c-Abl tyrosine kinase is activated in the apoptotic response of cells to DNA damage. The mechanisms by which c-Abl signals the induction of apoptosis are not understood. Here we show that c-Abl binds constitutively to the mammalian homolog of the Schizosaccharomyces pombe Rad9 cell cycle checkpoint protein. The SH3 domain of c-Abl interacts directly with the C-terminal region of Rad9. c-Abl phosphorylates the Rad9 Bcl-2 homology 3 domain (Tyr-28) in vitro and in cells exposed to DNA-damaging agents. The results also demonstrate that c-Abl-mediated phosphorylation of Rad9 induces binding of Rad9 to the antiapototic Bcl-xL protein. The regulation of Rad9 by c-Abl in the DNA damage response is further supported by the demonstration that the interaction between c-Abl and Rad9 contributes to DNA damage-induced apoptosis. These findings indicate that Rad9 is regulated by a c-Abl-dependent mechanism in the apoptotic response to genotoxic stress.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115. Phone: (617) 632-3141. Fax: (617) 632-2934. E-mail: donald_kufe{at}dfci.harvard.edu.

Molecular and Cellular Biology, May 2002, p. 3292-3300, Vol. 22, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.10.3292-3300.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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