Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation.
In normal human diploid fibroblasts, cyclins of the A, B, and D classes each associate with cyclin-dependent kinases (CDKs), proliferating cell nuclear antigen (PCNA), and p21, thereby forming multiple independent quaternary complexes. Upon transformation of diploid fibroblasts with the DNA tumor virus SV40, or its transforming tumor antigen (T), the cyclin D/p21/CDK/PCNA complexes are disrupted. In transformed cells, CDK4 totally dissociates from cyclin D, PCNA, and p21 and, instead, associates exclusively with a polypeptide of 16 kD (p16). Quaternary complexes containing cyclins A or B1 and p21/CDK/PCNA also undergo subunit rearrangement in transformed cells. Both PCNA and p21 are no longer associated with CDC2-cyclin B1 binary complexes. Cyclin A complexes no longer contain p21, and a new 19-kD polypeptide (p19) is found in association with cyclin A. The pattern of subunit rearrangement of cyclin-CDK complexes in SV40-transformed cells is also shared in those containing adeno- or papilloma viral oncoproteins. Rearrangement also occurs in p53-deficient cells derived from Li-Fraumeni patients that carry no known DNA tumor virus. These findings suggest a mechanism by which oncogenic proteins alter the cell cycle of transformed cells.
Xiong
Y
Y
Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, New York 11724.
Zhang
H
H
Beach
D
D
D000595:Amino Acid Sequence; D000818:Animals; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D002522:Chlorocebus aethiops; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D016213:Cyclins / Q000737:chemistry* / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts; D006367:HeLa Cells; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000201:enzymology; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry; D009687:Nuclear Proteins / Q000737:chemistry; D015689:Oncogene Protein p21(ras) / Q000737:chemistry / Q000378:metabolism; D015513:Oncogene Proteins / Q000737:chemistry* / Q000502:physiology*; D018809:Proliferating Cell Nuclear Antigen; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013539:Simian virus 40; D013329:Structure-Activity Relationship; D014170:Transformation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016213:Cyclins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; 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; D015689:Oncogene Protein p21(ras)