Cell Cycle Control: G1/S Checkpoint

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Pathway Description:

The primary G1/S cell cycle checkpoint controls the commitment of eukaryotic cells to transition through the “gap” phase (G1) and enter into the DNA synthesis phase (S). Two cell cycle kinase-complexes, CDK4/6-cyclin D and CDK2-cyclin E, work in concert to relieve inhibition of a dynamic transcription complex that contains Rb and E2F. During G1-phase in uncommitted cells, the Rb-HDAC repressor complex binds to the E2F-DP1 transcription factors, thus inhibiting key downstream transcription events. Phosphorylation of Rb by CDK4/6 and CDK2 dissociates the repressor complex from Rb, permitting transcription of key S-phase-promoting genes including some that are required for DNA replication. Recent evidence suggests that CDK2 also phosphorylates the transcription factor FoxO1, inhibiting its transcriptional activity and thereby negatively regulating the transcription of apoptotic genes post DNA damage. Notably, a multitude of different stimuli exert checkpoint control including TGF-β, DNA damage, contact inhibition, replicative senescence and growth factor withdrawal. To this end, these stimuli exert their action by inducing specific members of the INK4 or KIP/CIP families of cyclin dependent kinase inhibitors (CKIs). In this regard, TGF-β also inhibits the transcription of cdc25A, a phosphatase directly required for CDK activation. At a critical convergence point with the DNA-damage check-point, cdc25A is ubiquitinated and targeted for degradation via the SCF ubiquitin ligase complex downstream of ATM/ATR/Chk1/2 pathway. However, timely targeted degradation of cdc25A in mitosis (M-phase) via the APC ubiquitin ligase complex allows progression through mitosis. Importantly, growth factor withdrawal activates GSK-3β, which in turn phosphorylates cyclin D, leading to its rapid ubiquitination and proteosomal degradation. Collectively, ubiquitin/proteasome-dependent degradation and nuclear export are mechanisms commonly used to rapidly reduce the concentration of cell cycle control proteins. Some redundancy and tissue specific requirements exist as shown by animal models.

Selected Reviews:

• Bartek J, Lukas C, Lukas J (2004) Checking on DNA damage in S phase. Nat. Rev. Mol. Cell Biol. 5(10), 792–804.
• Busino L, Chiesa M, Draetta GF, Donzelli M (2004) Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis. Oncogene 23(11), 2050–6.
• Harbour JW, Dean DC (2000) The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 14(19), 2393–409.
• Pagano M, Jackson PK (2004) Wagging the dogma; tissue-specific cell cycle control in the mouse embryo. Cell 118(5), 535–8.
• Pavletich NP (1999) Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J. Mol. Biol. 287(5), 821–8.
• Pelengaris S, Khan M, Evan G (2002) c-MYC: more than just a matter of life and death. Nat. Rev. Cancer 2(10), 764–76.
• Malumbres M, Barbacid M (2001) To cycle or not to cycle: a critical decision in cancer. Nat. Rev. Cancer 1(3), 222–31.
• Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13(12), 1501–12.

CST would like to thank Dr. Hans Widlund, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, for contributing to this diagram.

created November 2002 • revised January 2007