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 G1 phase 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 the retinoblastoma protein, Rb, and E2F. In G1-phase uncommitted cells, hypo-phosphorylated Rb binds to the E2F-DP1 transcription factors in a repressive complex containing HDAC, thus inhibiting key downstream transcription events. Phosphorylation of Rb by Cyclin D-CDK4/6 and subsequently by Cyclin E-CDK2 dissociates the repressor complex from Rb, permitting transcription of key S-phase-promoting genes required for DNA replication. CDK2 may also phosphorylate FoxO1, which inhibits its transcriptional activity by nuclear export and allows for survival and proliferation. Importantly, a multitude of different stimuli exert checkpoint control, including TGF-β, DNA damage, replicative senescence, and growth factor withdrawal. These stimuli act though transcription factors to induce specific members of the INK4 or KIP/CIP families of cyclin dependent kinase inhibitors (CKIs). Mounting evidence implicates the polycomb protein BMI1 in negative regulation of INK4A/B in stem cells and cancer. In addition to regulating CKIs, TGF-β also inhibits cdc25A transcription, a phosphatase directly required for CDK activation. At a critical convergence point with the DNA-damage checkpoint, cdc25A is ubiquitinated and targeted for degradation via the SCF ubiquitin ligase complex downstream of ATM/ATR/Chk-pathway. However, timely degradation of cdc25A in mitosis (M-phase) via the APC ubiquitin ligase complex allows progression through mitosis. Furthermore, growth factor withdrawal activates GSK-3β, which in turn phosphorylates Cyclin D, leading to its rapid ubiquitination and proteasomal degradation. Collectively, ubiquitin/proteasome-dependent degradation and nuclear export are mechanisms commonly used to rapidly reduce the concentration of cell cycle control proteins.

Selected Reviews:

• Gil J, Peters G (2006) Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat. Rev. Mol. Cell Biol. 7(9), 667–77.
• Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer 9(3), 153–66.
• Skaar JR, Pagano M (2009) Control of cell growth by the SCF and APC/C ubiquitin ligases. Curr. Opin. Cell Biol. 21(6), 816–24.
• Sparmann A, van Lohuizen M (2006) Polycomb silencers control cell fate, development and cancer. Nat. Rev. Cancer 6(11), 846–56.
• van den Heuvel S, Dyson NJ (2008) Conserved functions of the pRB and E2F families. Nat. Rev. Mol. Cell Biol. 9(9), 713–24.
• Yang JY, Hung MC (2009) A new fork for clinical application: targeting forkhead transcription factors in cancer. Clin. Cancer Res. 15(3), 752–7.

We would like to thank Dr. Hans Widlund, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, for contributing to this diagram.