Mammalian Cell Cycle Progression

• A typical cell division results in the generation of two identical daughter cells. Soon after formation, daughter cells either enter a new round of the cell cycle or stop proliferation.
• If cells decide to cease to proliferate, they enter a phase called G0-phase (or quiescence) or undergo a differentiation program. The decision to differentiate is often dependent on developmental cues. 
• If the daughter cells decide to enter the cell cycle, they need mitogenic signaling until they reach a phase in the cell cycle called the “restriction point”. 
• The mitogenic control of cell cycle progression is lost during tumourigenesis and is considered a hallmark of cancer cells (Hanahan and Weinberg, 2000). In cultured primary cells, mitogenic signaling is the primary factor that is required for cells to progress through the G1 phase. In the absence of mitogenic signaling, these cells enter G0 (quiescence) phase.
• G1 phase progression involves mitogen-mediated synthesis of D-type cyclins and inactivation of Rb family proteins.
• Phosphorylation of Rb by CDK4/6-cyclin D as well as CDK2-cyclin E leads to its inactivation and release of E2F transcription factor that results in induction of S-phase gene transcription. 
• CDK2-cyclin E complex has also been reported to be involved in DNA replication initiation by facilitating the loading of MCM chromosome maintenance proteins onto the origin of replication. 
• CDK2-cyclin E complex is then silenced once cells enter S-phase. Silencing of CDK2-cyclin E complex is essential to avoid re-replication of DNA.
• CDK2-cyclin E phosphorylates its own inhibitor, p27, and induces its degradation, thereby regulating its own activity (positive Feedback loop).
• CDK2-cyclin E complex is inactivated by mainly degrading cyclin E. Cyclin E is rapidly degraded by SCF-Fbxw7 ubiquitin ligase, followed by its cleavage by the proteasome. 
• Studies from knockout mice show that CDK4 and CDK6 are not required for cell cycle entry after mitogenic stimuli.
• G1/S phase transition: APC/C is negatively regulated during S-phase by either Emi1 or degradation of Cdh1, leading to geminin stabilization and preventing DNA reduplication after replication origins have fired.
• S-phase progression: CDK2/Cyclin A complexes have been reported to regulate S-phase progression. It phosphorylates numerous proteins that are thought to be required for proper completion and exit from the S phase. At the end of S-phase cyclin A forms complex with CDK1.
• G2 phase progression: G2 phase progression is controlled by CDK1-cyclin A complex. 
• B-type cyclin synthesis starts at the end of the S-phase and continues in G2 phase. B-type cyclins (mainly cyclin B1) accumulate in the cytoplasm during G2 phase.
• Prophase: Cytoplasmic CDK1/Cyclin B complexes associate with centrosomes, where they promote centrosome separation. Phosphorylation of centrosome-associated motor protein Eg5 by CDK1-cyclin B complex is required for centrosome separation.
• Metaphase to anaphase transition: At the end of metaphase, all chromosomes must be bi-orientated on the metaphase and attached to the mitotic spindle. When all the chromosomes are properly oriented and SAC is satisfied (turned off), APC/C is activated. E2 enzyme UBE2C (ubiquitin-conjugating enzyme E2 C)/UbcH10 and p31Comet promote APC/C dependent Cdc20 ubiquitination, leading to the release of Cdc20 from the Mad2-BubR1 complex. Released Cdc20 binds to APC/C which promotes anaphase onset.
• Separation of Sister chromatids: Sister chromatids are bound together by cohesin protein. Cohesin degradation leads to the separation of sister chromatids. Separase activity is required for the degradation of cohesin. During metaphase, separase is kept inactive by two mechanisms. First by its inhibitor securin and other by phosphorylation and direct binding of CDK1-cyclin B1 complex.
• Mitotic exit: Activation Cdh1 is required for mitotic exit. Cdh1 is kept inactive during metaphase by phosphorylation. This inhibitory phosphorylation required Cyclin B1-CDK1 activity. At the onset of anaphase, Cyclin B1 is degraded which results in loss of CDK1 activity. Active mitotic phosphatases during this phase then remove this inhibitory phosphate which ultimately leads to the formation of an active APC/C-Cdh1 complex. The mitotic phosphatases which are required for dephosphorylation of CDK1 substrate remain unknown. in most of the organisms.

REFERENCES:

• Malumbres & Barbacid, 2005. Mammalian cyclin-dependent kinases. Trends Biochem Sci. 30(11), 630-41. PMID-16236519; Full-Text Links: Cell