Etoposide and adriamycin but not genistein can activate the checkpoint kinase Chk2 independently of ATM/ATR

Biochem Biophys Res Commun. 2001 Dec 21;289(5):1199-204. doi: 10.1006/bbrc.2001.6095.

Abstract

We have investigated the effects of three unrelated topoisomerase 2 inhibitors, genistein, adriamycin, and etoposide, on phosphorylation/activation of the checkpoint kinase Chk2 in normal or ATM-deficient (ATM-) human fibroblasts and in cells overexpressing a catalytically inactive ATR kinase. We demonstrate that genistein activates Chk2 in a strictly ATM-dependent manner, whereas etoposide and adriamycin can trigger Chk2 activation in long-term cultures of ATM- cells. Moreover, these two latter genotoxic compounds were found to activate Chk2 in fibroblasts expressing the dominant negative form of ATR. We also report a significant decrease in the accumulation in G2-phase of ATM- cells when genistein did not activate Chk2. In conclusion, our results strongly support that activation of Chk2 could be dependent on the type and/or extent of DNA damage and under the control of either an ATM-dependent or an ATM and, maybe, an ATR-independent pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia / genetics
  • Ataxia Telangiectasia / metabolism
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins*
  • Cell Line
  • Checkpoint Kinase 2
  • DNA Damage
  • DNA-Binding Proteins
  • Doxorubicin / pharmacology*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Etoposide / pharmacology*
  • G2 Phase
  • Genistein / pharmacology
  • Humans
  • Mutagens / pharmacology
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Topoisomerase II Inhibitors
  • Tumor Suppressor Proteins

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Mutagens
  • Topoisomerase II Inhibitors
  • Tumor Suppressor Proteins
  • Etoposide
  • Doxorubicin
  • Genistein
  • Protein Kinases
  • Checkpoint Kinase 2
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK2 protein, human
  • Protein-Serine-Threonine Kinases