c-Abl tyrosine kinase regulates the human Rad9 checkpoint protein in response to DNA damage

Mol Cell Biol. 2002 May;22(10):3292-300. doi: 10.1128/MCB.22.10.3292-3300.2002.

Abstract

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-x(L) 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / physiology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • DNA Damage*
  • Flow Cytometry
  • Humans
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins c-abl / genetics
  • Proto-Oncogene Proteins c-abl / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transfection
  • Tyrosine / metabolism
  • bcl-X Protein

Substances

  • BCL2L1 protein, human
  • Cell Cycle Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Fusion Proteins
  • bcl-X Protein
  • rad9 protein
  • Tyrosine
  • Proto-Oncogene Proteins c-abl