Skip to main content

Chromium (VI) activates ataxia telangiectasia mutated (ATM) protein. Requirement of ATM for both apoptosis and recovery from terminal growth arrest.

Publication ,  Journal Article
Ha, L; Ceryak, S; Patierno, SR
Published in: J Biol Chem
May 16, 2003

The ataxia telangiectasia mutated (ATM) protein plays a central role in early stages of DNA double strand break (DSB) detection and controls cellular responses to this damage. Although hypersensitive to ionizing radiation-induced clonogenic lethality, ataxia telangiectasia cells are paradoxically deficient in their ability to undergo ionizing radiation-induced apoptosis. This contradiction illustrates the complexity of the central role of ATM in DNA damage response and the need for further understanding. Certain hexavalent chromium (Cr(VI)) compounds are implicated as occupational respiratory carcinogens at doses that are both genotoxic and cytotoxic. Cr(VI) induces a broad spectrum of DNA damage, but Cr(VI)-induced DSBs have not been reported. Here, we examined the role of ATM in the cellular response to Cr(VI) and found that Cr(VI) activates ATM. We also show that physiological targets of ATM, p53 Ser-15 and Chk2 Thr-68, were phosphorylated by Cr(VI) exposure in an ATM-dependent fashion. We found that ATM-/- cells were markedly resistant to Cr(VI)-induced apoptosis but considerably more sensitive to Cr(VI)-induced clonogenic lethality than wild type cells, indicating that resistance to Cr(VI)-induced apoptosis did not confer a selective survival advantage. However, analysis of long term growth arrest revealed a striking difference: ATM-/- cells were markedly less able to recover from Cr(VI)-induced growth arrest. This indicates that terminal growth arrest is the fate of these apoptosis-resistant cells. In summary, ATM is involved in cellular response to a complex genotoxin that may not directly induce DSBs. Our data suggest that ATM is a major signal initiator for genotoxin-induced apoptosis but, paradoxically, also contributes to maintenance of cell survival by facilitating recovery/escape from terminal growth arrest. The results also strongly suggest that terminal growth arrest is not merely an extended or even irreversible form of checkpoint arrest, but instead an independent and unique cell fate pathway.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

May 16, 2003

Volume

278

Issue

20

Start / End Page

17885 / 17894

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Time Factors
  • Threonine
  • Sodium Compounds
  • Serine
  • Protein Transport
  • Protein Serine-Threonine Kinases
  • Protein Kinases
  • Phosphorylation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Ha, L., Ceryak, S., & Patierno, S. R. (2003). Chromium (VI) activates ataxia telangiectasia mutated (ATM) protein. Requirement of ATM for both apoptosis and recovery from terminal growth arrest. J Biol Chem, 278(20), 17885–17894. https://doi.org/10.1074/jbc.M210560200
Ha, Linan, Susan Ceryak, and Steven R. Patierno. “Chromium (VI) activates ataxia telangiectasia mutated (ATM) protein. Requirement of ATM for both apoptosis and recovery from terminal growth arrest.J Biol Chem 278, no. 20 (May 16, 2003): 17885–94. https://doi.org/10.1074/jbc.M210560200.
Ha, Linan, et al. “Chromium (VI) activates ataxia telangiectasia mutated (ATM) protein. Requirement of ATM for both apoptosis and recovery from terminal growth arrest.J Biol Chem, vol. 278, no. 20, May 2003, pp. 17885–94. Pubmed, doi:10.1074/jbc.M210560200.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

May 16, 2003

Volume

278

Issue

20

Start / End Page

17885 / 17894

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Time Factors
  • Threonine
  • Sodium Compounds
  • Serine
  • Protein Transport
  • Protein Serine-Threonine Kinases
  • Protein Kinases
  • Phosphorylation