Oncogenic pathways impinging on the G2-restriction point.
In the absence of mitogenic stimuli, cells normally arrest in G(1/0), because they fail to pass the G1-restriction point. However, abrogation of the G1-restriction point (by loss of the retinoblastoma gene family) reveals a second-restriction point that arrests cells in G2. Serum-starvation-induced G2 arrest is effectuated through inhibitory interactions of p27(KIP1) and p21(CIP1) with cyclins A and B1 and can be reversed through mitogen re-addition. In this study, we have investigated the pathways that allow cell cycle re-entry from this G2 arrest. We provide evidence that recovery from G2 arrest depends on the rat sarcoma viral oncogene (RAS) and phosphatidylinositol-3 kinase pathways and show that oncogenic hits, such as overexpression of c-MYC or mutational activation of RAS can abrogate the G2-restriction point. Together, our results provide new mechanistic insight into multistep carcinogenesis.
Foijer
F
F
Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Simonis
M
M
van Vliet
M
M
Wessels
L
L
Kerkhoven
R
R
Sorger
P K
PK
Te Riele
H
H
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016195:G2 Phase / Q000502:physiology*; D020869:Gene Expression Profiling; D011905:Genes, ras / Q000502:physiology; D051379:Mice; D005810:Multigene Family / Q000502:physiology; D009857:Oncogenes / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology
D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins