Eukaryotic cell cycles are divided into four discrete phases: M, G1, S, and G2. M phase consists of mitosis, which is usually followed by cytokinesis. S phase is the period of DNA replication. Progression through the cell cycle is regulated by extracellular signals, such as growth factors. Checkpoints and feedback controls coordinate the events that take place during different phases of the cell cycle and arrest cell cycle progression if DNA is damaged.
MPF, the key molecule responsible for regulating the G2 to M transition, is a dimer of the Cdk1 protein kinase and cyclin B. Distinct pairs of cyclins and Cdk1-related protein kinases regulate progression through different stages of the cell cycle. The activity of Cdk's is regulated by association with cyclins, phosphorylation, and Cdk inhibitors. Growth factors stimulate animal cell proliferation by inducing synthesis of the D-type cyclins, which associate with Cdk4 and Cdk6 in G1. A key substrate of Cdk4, 6/cyclin D complexes is the tumor suppressor protein Rb, which regulates transcription of genes required for cell cycle progression, including cyclin E. Activation of Cdk2/cyclin E complexes and inhibition of the APC/C ubiquitin ligase is then responsible for entry into S phase. Cdk2/cyclin E initiates DNA replication by activating the MCM helicase at origins of replication. Arrest of the cell cycle in response to DNA damage is mediated by protein kinases that inhibit Cdc25 phosphatases, which are required for Cdk activation. In mammalian cells, arrest at the G1 checkpoint is also mediated by p53, which induces synthesis of the Cdk inhibitor p21.
M phase is initiated by activation of Cdk1/cyclin B, Aurora, and Polo-like kinases, which are responsible for chromatin condensation, nuclear envelope breakdown, fragmentation of the Golgi apparatus, and reorganization of microtubules to form the mitotic spindle. The attachment of spindle microtubules to the kinetochores of sister chromatids then leads to their alignment on the metaphase plate. Activation of the APC/C ubiquitin ligase leads to the metaphase to anaphase transition. The activity of APC/C is inhibited by the spindle assembly checkpoint until all chromosomes are properly aligned on the spindle. Ubiquitin-mediated proteolysis initiated by the APC/C then leads to the degradation of cohesin, breaking the link between sister chromatids at the onset of anaphase. The APC/C also ubiquitylates cyclin B, leading to inactivation of Cdk1, exit from mitosis, and cytokinesis.