Mitogen requirement for cell cycle progression in the absence of pocket protein activity.
Primary mouse embryonic fibroblasts lacking expression of all three retinoblastoma protein family members (TKO MEFs) have lost the G1 restriction point. However, in the absence of mitogens these cells become highly sensitive to apoptosis. Here, we show that TKO MEFs that survive serum depletion pass G1 but completely arrest in G2. p21CIP1 and p27KIP1 inhibit Cyclin A-Cdk2 activity and sequester Cyclin B1-Cdk1 in inactive complexes in the nucleus. This response is alleviated by mitogen restimulation or inactivation of p53. Thus, our results disclose a cell cycle arrest mechanism in G2 that restricts the proliferative capacity of mitogen-deprived cells that have lost the G1 restriction point. The involvement of p53 provides a rationale for the synergism between loss of Rb and p53 in tumorigenesis.
Foijer
Floris
F
Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Wolthuis
Rob M F
RM
Doodeman
Valerie
V
Medema
René H
RH
te Riele
Hein
H
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D019925:Cyclin A / Q000037:antagonists & inhibitors / Q000378:metabolism; D019926:Cyclin B / Q000187:drug effects / Q000378:metabolism; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000494:pharmacology; D004249:DNA Damage; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008934:Mitogens / Q000494:pharmacology / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000502:physiology*; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000502:physiology*; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C534700:Ccnb1 protein, mouse; D019925:Cyclin A; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008934:Mitogens; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016203:CDC2 Protein Kinase