ATM is required for rapid degradation of cyclin D1 in response to gamma-irradiation.
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.
Choo
Dong Wan
DW
Radiation Medicine Branch, National Cancer Center, Goyang-si, Gyeonggi-do, South Korea.
Baek
Hye Jung
HJ
Motoyama
Noboru
N
Cho
Kwan Ho
KH
Kim
Hye Sun
HS
Kim
Sang Soo
SS
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism* / Q000528:radiation effects*; D003513:Cycloheximide / Q000494:pharmacology; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005720:Gamma Rays; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
C530104:CCND1 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011500:Protein Synthesis Inhibitors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D019938:Cyclin D1; D003513:Cycloheximide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3