Permanent growth arrest in irradiated human fibroblasts.
Exposure of human fibroblasts to doses of ionizing radiation sufficient to cause a permanent growth arrest repressed the expression of genes induced late during G(0)/G(1)-phase traverse, including both cyclin A and cyclin E. In addition, radiation prevented the cell cycle-dependent activation of cyclin D1-associated kinase activity and the subsequent phosphorylation of the RB tumor suppressor protein. Exposure to radiation did not alter the cellular levels of cyclin D1 protein, nor did it alter the formation of cyclin D1-CDK4 complexes. Surprisingly, the repression of cyclin D1-associated kinase activity in damaged mitogen-stimulated quiescent cells could not be accounted for by a relative increase in the association of CDKN1A (also known as p21(Cip1)) with cyclin D1 complexes, nor was cyclin D1 activity targeted by increased levels of CDKN1A in irradiated, logarithmically growing cultures under conditions where cyclin A activity was acutely repressed. Therefore, a radiation-induced permanent growth arrest is mediated by pathways that are distinct from those that cause cell cycle delay in damaged cells involving repression of cyclin-dependent kinase activity by CDKN1A.
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Oncology, University of South Florida College of Medicine, 12902 Magnolia Drive, Tampa, FL 33612, USA.
J
J
Savell
S
S
Rao
W J
WJ
Pledger
W
W
Wharton
D002455:Cell Division / Q000528:radiation effects; D002478:Cells, Cultured / Q000166:cytology / Q000528:radiation effects; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000528:radiation effects*; D016193:G1 Phase / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000528:radiation effects; D018816:Genes, cdc; D006801:Humans; D046911:Macromolecular Substances; D008934:Mitogens / Q000494:pharmacology; D010766:Phosphorylation / Q000528:radiation effects; D011499:Protein Processing, Post-Translational / Q000528:radiation effects; D011518:Proto-Oncogene Proteins; D016192:Resting Phase, Cell Cycle / Q000528:radiation effects; D016160:Retinoblastoma Protein / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D046911:Macromolecular Substances; D008934:Mitogens; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases