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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 to enter into the DNA synthesis S phase. 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 forming an inhibitory complex with HDAC to repress key downstream transcription events. Commitment to enter S-phase occurs through sequential phosphorylation of Rb by Cyclin D-CDK4/6 and Cyclin E-CDK2 that dissociates the HDAC-repressor complex, permitting transcription of genes required for DNA replication. In the presence of growth factors, Akt can phosphorylate FoxO1/3, which inhibits their function by nuclear export, thereby allowing cell 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). Notably, the oncogenic polycomb protein Bmi1 acts as a negative regulator of INK4A/B expression in stem cells and human 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 the 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 to phosphorylate Cyclin D, which leads to its rapid ubiquitination and proteasomal degradation. Collectively, ubiquitin/proteasome-dependent degradation and nuclear export are mechanisms commonly used to effectively reduce the concentration of cell cycle control proteins. Importantly, Cyclin D1/CKD4/6 complexes are explored as therapeutic targets for cancer treatment as researchers have found this checkpoint to be invariantly deregulated in human tumors.

Selected Reviews:

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

created November 2002

revised November 2012