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.
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Acknowledgements
We thank T Ouchi for helpful discussion, the technical help of K-T Kim, and W Wong and M Meyer for proof-reading the manuscript. This work was supported in part by Grants CA85681 and CA78356.
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Ohtsuka, T., Jensen, M., Kim, H. et al. The negative role of cyclin G in ATM-dependent p53 activation. Oncogene 23, 5405–5408 (2004). https://doi.org/10.1038/sj.onc.1207693
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DOI: https://doi.org/10.1038/sj.onc.1207693
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