Overexpression of cyclin D1 blocks proliferation of normal diploid fibroblasts.
Human cyclin D1 forms complexes with several Cdks, with proliferating cell nuclear antigen, and with a recently discovered 21-kDa inhibitor of Cdk activity. Substrates for cyclin D1/Cdks have not been identified in vivo, but it has been proposed that the D class of cyclins might play a role in regulating the activity of the retinoblastoma gene product p105Rb. Here we report that normal human diploid fibroblasts that endogenously or ectopically express high levels of cyclin D1 are unable to enter S phase in response to normally mitogenic stimuli. Fibroblasts that have reached the end of their in vitro life span (senescent cells) express five-fold higher levels of cyclin D1 protein than low-passage cells and individual cells in mass culture that fail to initiate DNA synthesis in response to serum addition have severalfold higher levels of this cyclin than proliferation-competent cells. These observations provide evidence that cyclin D1 is involved with the regulation of cell proliferation by more than one mechanism.
Atadja
P
P
Department of Medical Biochemistry, University of Calgary, Alberta.
Wong
H
H
Veillete
C
C
Riabowol
K
K
D001483:Base Sequence; D001769:Blood; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D002461:Cell Line, Transformed; D016922:Cellular Senescence / Q000502:physiology; D003001:Cloning, Molecular; D019938:Cyclin D1; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis; D017931:DNA Primers; D004171:Diploidy; D005347:Fibroblasts / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D008938:Mitosis / Q000502:physiology; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016196:S Phase / Q000502:physiology
D016213:Cyclins; D017931:DNA Primers; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases