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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Baskaran, R; Wood, LD; Whitaker, LL; Canman, CE; Morgan, SE; Xu, Y; Barlow, C; Baltimore, D; Wynshaw-Boris, A; Kastan, MB; Wang, JY

Published Date

  • May 29, 1997

Published In

Volume / Issue

  • 387 / 6632

Start / End Page

  • 516 - 519

PubMed ID

  • 9168116

Pubmed Central ID

  • 9168116

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/387516a0

Language

  • eng

Conference Location

  • England