PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2

Nat Cell Biol. 2002 Nov;4(11):865-70. doi: 10.1038/ncb869.

Abstract

The promyelocytic leukaemia (PML) gene is translocated in most acute promyelocytic leukaemias and encodes a tumour suppressor protein. PML is involved in multiple apoptotic pathways and is thought to be pivotal in gamma irradiation-induced apoptosis. The DNA damage checkpoint kinase hCds1/Chk2 is necessary for p53-dependent apoptosis after gamma irradiation. In addition, gamma irradiation-induced apoptosis also occurs through p53-independent mechanisms, although the molecular mechanism remains largely unknown. Here, we report that hCds1/Chk2 mediates gamma irradiation-induced apoptosis in a p53-independent manner through an ataxia telangiectasia-mutated (ATM)-hCds1/Chk2-PML pathway. Our results provide the first evidence of a functional relationship between PML and a checkpoint kinase in gamma irradiation-induced apoptosis.

MeSH terms

  • Adenoviridae / genetics
  • Apoptosis*
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins
  • Cell Nucleus / metabolism
  • Checkpoint Kinase 2
  • DNA Damage
  • DNA-Binding Proteins
  • Dose-Response Relationship, Radiation
  • Electroporation
  • Gamma Rays
  • Glutathione Transferase / metabolism
  • HeLa Cells
  • Humans
  • Microscopy, Confocal
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / physiology*
  • Nuclear Proteins*
  • Phosphorylation
  • Plasmids / metabolism
  • Precipitin Tests
  • Promyelocytic Leukemia Protein
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Recombinant Fusion Proteins / metabolism
  • Serine / chemistry
  • Time Factors
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transfection
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins
  • U937 Cells

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • Promyelocytic Leukemia Protein
  • Recombinant Fusion Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • PML protein, human
  • Serine
  • Glutathione Transferase
  • Checkpoint Kinase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK2 protein, human
  • Protein-Serine-Threonine Kinases