Genotoxic drugs induce interaction of the c-Abl tyrosine kinase and the tumor suppressor protein p53.

Overview

The function of the c-Abl protein tyrosine kinase is unknown. The present studies demonstrate that the antimetabolite 1-beta-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.