The negative role of cyclin G in ATM-dependent p53 activation.
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.
Ohtsuka
Takao
T
Cancer Biology Program, Hematology/Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Jensen
Michael R
MR
Kim
Hyung Gu
HG
Kim
Kyung-Tae
KT
Lee
Sam W
SW
D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000378:metabolism / Q000502:physiology*; D004249:DNA Damage; D004268:DNA-Binding Proteins; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012694:Serine / Q000737:chemistry; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
C534702:CCNG1 protein, human; D018797:Cell Cycle Proteins; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D012694:Serine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases