The negative role of cyclin G in ATM-dependent p53 activation

Oncogene. 2004 Jul 8;23(31):5405-8. doi: 10.1038/sj.onc.1207693.

Abstract

Cyclin G is one of the earliest p53 target genes to be identified, but its function in the p53 pathway has been elusive. Although the precise mechanisms of cyclin G in this novel network have not been explored, recent studies have demonstrated that cyclin G is a key regulator of the p53-Mdm2 network. Here we present evidence that cyclin G-mediated p53 regulation is dependent upon the status of ataxia-telangiectasia mutated (ATM) protein, which activates p53 in response to DNA damage. Abrogation of cyclin G enhances p53 accumulation and phosphorylation of p53 at the Ser-15 residue, resulting in cell cycle arrest. Ectopically expressed cyclin G significantly reduces the steady-state levels of p53 as well as that of phosphorylated p53 at Ser-15 after DNA damage in normal human dermal fibroblasts containing normal ATM. However, cyclin G does not cause similar reductions in p53 levels in ATM-mutated cells. We also show that translocation of cyclin G to the nucleus requires functional ATM. Thus, our findings identify a new role of cyclin G in ATM-dependent p53 regulation and in cell cycle regulation during DNA damage.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle
  • Cell Cycle Proteins
  • Cyclin G
  • Cyclin G1
  • Cyclins / metabolism
  • Cyclins / physiology*
  • DNA Damage
  • DNA-Binding Proteins
  • Flow Cytometry
  • Green Fluorescent Proteins
  • Humans
  • Luminescent Proteins / metabolism
  • Mutation
  • Phosphorylation
  • Plasmids / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • Serine / chemistry
  • Transfection
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins

Substances

  • CCNG1 protein, human
  • Cell Cycle Proteins
  • Cyclin G
  • Cyclin G1
  • Cyclins
  • DNA-Binding Proteins
  • Luminescent Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Green Fluorescent Proteins
  • Serine
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases