ATM is required for rapid degradation of cyclin D1 in response to {gamma}-irradiation
- Radiation Medicine Branch, National Cancer Center, 809 Madu 1-dong, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769 (Korea, Republic of)
- Department of Geriatric Research, National Institute for Longevity Sciences, Morioka, Obu (Japan)
- Department of Biological Science, Ajou University, Suwon, Gyeonggi (Korea, Republic of)
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-3{beta} phosphorylation site, the mutant protein showed resistance to irradiation-induced proteolysis although inhibitors of GSK-3{beta} 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.
- OSTI ID:
- 21255850
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 378, Issue 4; Other Information: DOI: 10.1016/j.bbrc.2008.11.132; PII: S0006-291X(08)02371-1; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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