| 19071090 |
Choo DW, Baek HJ, Motoyama N, Cho KH, Kim HS, Kim SS: ATM is required for rapid degradation of cyclin D1 in response to gamma-irradiation. Biochem Biophys Res Commun. 2009 Jan 23;378(4):847-50. Epub 2008 Dec 9.
The cellular response to DNA damage induced by gamma-irradiation activates cell-cycle arrest to permit DNA repair and to prevent replication. Cyclin D1 is the key molecule for transition between the G1 and S phases of the cell-cycle, and amplification or overexpression of cyclin D1 plays pivotal roles in the development of several human cancers. To study the regulation of cyclin D1 in the DNA-damaged condition, we analyzed the proteolytic regulation of cyclin D1 expression upon gamma-irradiation. Upon gamma-irradiation, a rapid reduction in cyclin D1 levels was observed prior to p53 stabilization, indicating that the stability of cyclin D1 is controlled in a p53-independent manner. Further analysis revealed that irradiation facilitated ubiquitination of cyclin D1 and that a proteasome inhibitor blocked cyclin D1 degradation under the same conditions. Interestingly, after mutation of threonine residue 286 of cyclin D1, which is reported to be the GSK-3beta phosphorylation site, the mutant protein showed resistance to irradiation-induced proteolysis although inhibitors of GSK-3beta failed to prevent cyclin D1 degradation. Rather, ATM inhibition markedly prevented cyclin D1 degradation induced by gamma-irradiation. Our data indicate that communication between ATM and cyclin D1 may be required for maintenance of genomic integrity achieved by rapid arrest of the cell-cycle, and that disruption of this crosstalk may increase susceptibility to cancer. |
7(0,0,0,7) |