Genotoxic drugs induce interaction of the c-Abl tyrosine kinase and the tumor suppressor protein p53.
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.
Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Z M
ZM
Yuan
Y
Y
Huang
M M
MM
Fan
C
C
Sawyers
S
S
Kharbanda
D
D
Kufe
D002460:Cell Line; D003561:Cytarabine / Q000494:pharmacology; D004249:DNA Damage; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D009153:Mutagens; D016159:Tumor Suppressor Protein p53; D003561:Cytarabine; D008741:Methyl Methanesulfonate; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl