CDK redundancy guarantees cell cycle progression in Rb-negative tumor cells independently of their p16 status.
A high percentage of tumor cells bear mutations in the Rb tumor suppressor gene. They have high levels of the cdk inhibitor p16(ink4a) and no cyclin D/cdk4-6 complexes. Although p16 is known not to arrest the proliferation of Rb-negative cells, it is not known whether its presence affects how their cycle progresses, how E2F-dependent transcription is modulated, and whether and how Rb-related proteins are inactivated. We have assessed the relevance of p16(ink4a) for cell cycle progression of these cells. Using SaOS2 osteosarcoma cells as a model, we find that downregulation of p16(ink4a) by RNAi and reconstitution of active cyclin D/cdk4 complexes does not affect progression of the cycle of these cells or expression of E2F-dependent genes. Rb-negative tumor cells can functionally inactivate Rb-related proteins in G(1)/S transition independently of their p16(ink4a) status. Furthermore, Rb-negative tumor cells do not arrest when cdk1, cdk2 or cdk3 are inhibited by RNAi, independently of their p16(ink4a) status, and combined inhibition of these cdks is also not enough to arrest their cell cycle. However, cell cycle progression of Rb-negative tumor cells is sensitive to complete cdk inhibition, as it is arrested by the chemical cdk inhibitor roscovitine and the biological cdk inhibitor p27. These results suggest that, despite their lack of cyclin D-containing complexes, Rb-negative tumor cells, like normal untransformed cells, take advantage of the high degree of redundancy of cdks for their cell cycle progression.
Santamariña
Marta
M
Department of Physiology, School of Medicine, University of Santiago de Compostela, Spain.
Hernández
Gonzalo
G
Zalvide
Juan
J
D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D012516:Osteosarcoma / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000378:metabolism*; D000077546:Roscovitine
D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D047428:Protein Kinase Inhibitors; D011687:Purines; D016160:Retinoblastoma Protein; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases