Requirements for cell cycle arrest by p16INK4a

Analysis of tumor-derived mutations has led to the suggestion that p16INK4a, cyclin D1, cdk4, and the retinoblastoma protein (pRB) are components of a regulatory pathway that is inactivated in most tumor cells. Cell cycle arrest induced by p16INK4a, an inhibitor of cyclin D-dependent kinases, requir...

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Bibliographic Details
Published in:Molecular cell 2000-09, Vol.6 (3), p.737-742
Main Authors: Bruce, J L, Hurford, Jr, R K, Classon, M, Koh, J, Dyson, N
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Carrier Proteins - analysis
Carrier Proteins - genetics
Cells, Cultured
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinases - analysis
Fetus - cytology
Fibroblasts - chemistry
Fibroblasts - cytology
G1 Phase - physiology
Gene Expression Regulation, Neoplastic - physiology
Mice
Mice, Knockout
Nuclear Proteins - genetics
Phosphoproteins - genetics
Proteins
Proto-Oncogene Proteins
Retinoblastoma Protein - genetics
Retinoblastoma-Like Protein p107
Retinoblastoma-Like Protein p130
S Phase - physiology
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Summary:Analysis of tumor-derived mutations has led to the suggestion that p16INK4a, cyclin D1, cdk4, and the retinoblastoma protein (pRB) are components of a regulatory pathway that is inactivated in most tumor cells. Cell cycle arrest induced by p16INK4a, an inhibitor of cyclin D-dependent kinases, requires pRB, and it has been proposed that this G1 arrest is mediated by pRB-E2F repressor complexes. By comparing the properties of primary mouse embryonic fibroblasts specifically lacking pRB-family members, we find that pRB is insufficient for a p16INK4a-induced arrest. In addition to pRB, a second function provided by either p107 or p130, two pRB-related proteins, is required for p16INK4a to block DNA synthesis. We infer that p16INK4a-induced arrest is not mediated exclusively by pRB, but depends on the nonredundant functions of at least two pRB-family members.
ISSN:1097-2765
DOI:10.1016/S1097-2765(00)00072-1