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Volume 271, Number 43, Issue of October 25, 1996 pp. 26457-26460
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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COMMUNICATION:
Genotoxic Drugs Induce Interaction of the c-Abl Tyrosine Kinase and the Tumor Suppressor Protein p53

(Received for publication, July 29, 1996)

Zhi-Min Yuan , Yinyin Huang , Min-Min Fan , Charles Sawyers , Surender Kharbanda and Donald Kufe

From the Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 and the  Molecular Biology Institute, Department of Medicine, University of California, Los Angeles, California 90095

The function of the c-Abl protein tyrosine kinase is unknown. The present studies demonstrate that the antimetabolite 1--D-arabinofuranosylcytosine (ara-C) induces binding of c-Abl and p53. Ara-C treatment of cells that express wild type or a dominant negative, kinase-inactive c-Abl(K-R) was associated with formation of c-Abl-p53 complexes and increased expression of the cyclin-dependent kinase (Cdk) inhibitor p21. However, down-regulation of Cdk2 by ara-C was found in cells expressing wild type c-Abl and not in cells expressing c-Abl(K-R) or those deficient in p53. Similar findings were obtained following treatment of cells with the alkylating agent methyl methanesulfonate (MMS). Cells that express the c-Abl dominant negative or are null for c-Abl exhibited partial abrogation of Cdk2 down-regulation and G1 arrest in response to MMS exposure. Cells lacking the c-abl gene also responded to ara-C and MMS with increases in p53 levels and induction of p21. These findings indicate that the cellular response to certain genotoxic drugs involves binding of c-Abl to p53 and down-regulation of Cdk2 by a c-Abl kinase/p53-dependent mechanism.

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