Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation

Nature. 1997 May 29;387(6632):516-9. doi: 10.1038/387516a0.

Abstract

Ataxia telangiectasia (AT) is a rare human autosomal recessive disorder with pleiotropic phenotypes, including neuronal degeneration, immune dysfunction, premature ageing and increased cancer risk. The gene mutated in AT, ATM, encodes a putative lipid or protein kinase. Most of the human AT patient phenotypes are recapitulated in Atm-deficient mice. Cells derived from Atm-/- mice, like those from AT patients, exhibit abnormal response to ionizing radiation. One of the known responses to ionizing radiation is the activation of a nuclear tyrosine kinase encoded by the c-abl proto-oncogene. Ionizing radiation does not activate c-Abl in cells from AT patients or in thymocytes or fibroblasts from the Atm-deficient mice. Ectopic expression of a functional ATM kinase domain corrects this defect, as it phosphorylates the c-Abl tyrosine kinase in vitro at Ser 465, leading to the activation of c-Abl. A mutant c-Abl with Ser 465 changed to Ala 465 is not activated by ionizing radiation or ATM kinase in vivo. These findings identify the c-Abl tyrosine kinase as a downstream target of phosphorylation and activation by the ATM kinase in the cellular response to ionizing radiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Ataxia Telangiectasia / enzymology*
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle
  • Cell Cycle Proteins
  • Cell Line, Transformed
  • DNA-Binding Proteins
  • Enzyme Activation / radiation effects
  • Gamma Rays
  • Humans
  • Mice
  • Protein-Serine-Threonine Kinases*
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins c-abl / metabolism*
  • RNA Polymerase II / metabolism
  • Transfection
  • Tumor Suppressor Proteins

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Proteins
  • Tumor Suppressor Proteins
  • Proto-Oncogene Proteins c-abl
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • RNA Polymerase II