Cell Cycle: G1/S Checkpoint Regulation

In Eukaryotic cells, cell cycle checkpoint regulation ensures the fidelity of cell division. This kind of control verifies whether the processes at each phase of the cell cycle have been accurately completed before progression into the next phase. Mitogen-dependent progression through the first gap phase (G1) of the mammalian cell-division cycle is precisely regulated so that normal cell division is synchronous with cell growth. Also, the initiation of DNA synthesis (S phase) has to be timed precisely to avoid inappropriate DNA amplification which can result in genomic instability. The G1/S cell cycle checkpoint controls the passage of eukaryotic cells from the G1 into the S phase.The key components involved in the G1/S checkpoint are the cell cycle kinases, CDK4/6-cyclin D and CDK2-cyclin E, and the transcription complex that includes the retinoblastoma protein (Rb) and transcription factor E2F. The retinoblastoma protein is a nuclear phosphoprotein that regulates growth in the G1 phase of the cell cycle. Hypophosphorylated Rb exerts its growth-inhibitory effects by inhibiting critical regulatory proteins like E2F. The activation of E2F is necessary for the G1-S transition. Phosphorylation of Rb by CDK4/6-cyclin D and CDK2-cyclin E appears to release E2F and another trans factor DP-1 from an inhibitory complex, enabling them to promote the transcription necessary for progression into late G1 and S phase.Several stimuli exert check point control. These include transforming growth factor β (TGFβ), DNA damage, UV stress, replicative senescence, growth factor withdrawal and contact inhibition. Check point control largely involves the phosphorylation and inhibition of CDK4/6 and CDK2 by the INK4 and Cip/Kip family of cell cycle kinase inhibitors. TGFβ exerts additional checkpoint control by repressing the transcription of the phosphatase CDC25, which is an activator of cell cycle kinases. Growth factor removal activates Glycogen synthase kinase β (GSKβ), which in turn phosphorylates Cyclin D and marks it for ubiquitination. Ubiquitination and degradation of cyclins D and E by the Skp, Cullin, F-box containing complex (SCF complex) is another mechanism of checkpoint control.The G1/S checkpoint control is vital in normal cell division Mutations in the check point proteins can lead to apoptosis or tumorigenesis. This pathway highlights the key components of the G1/S checkpoint regulation.