Mitosis: Biochemical Pathways

By Levi Clancy for Student Reader on
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cell cycle mitosis biochemical pathway cyclin cdks

An obvious advantage of proteolysis for controlling passage through these critical points in the cell cycle is that protein degradation is an irreversible process, ensuring that cells proceed irreversibly in one direction through the cycle.

StepInitiationOverview
Early G1DNA prepreplication complexes assemble at origins. However, they are not activated. Mitotic cyclin-CDKs activate early steps in mitosis.
G0Most cells pause midway at a so-called G0 interphase to carry out their functions for most or all of their existence.
Mid G1G1 cyclin-CDK inactivates human Cdh2 and human inhibitors of cyclin-dependent kinase 4 and 6 (INK4s), important tumor suppressors that inhibit passage through G1 by inhibiting the mid G1 cyclin-CDKs. Both genes encoding INK4a are mutated in many human tumors, as they are less able to inhibit passage into G1.E2F is a critical transcription factor that is bound by its inhibitor, Rb. Mid G1 Cyclin-CDKs phosphorylate Rb, thus releasing it from E2F. This activated E2F stimulates expression of late G1 cyclin and CDK, S phase cyclin, and factors needed for DNA synthesis.
Late G1E2F stimulates its own transcription, and the Late-G1-cyclin+CDK can phosphorylate Rb; this forms a positive feedback loop whereby mid-G1 cyclin-CDKs are no longer needed to enter S-phase.Late-G1-cyclin+CDK activates expression of S-cyclin+CDK subunits. However, S-cyclin+CDK is promptly bound by its inhibitor Sic1.
S PhaseLate-G1-cyclin+CDK phosphorylates the S-cyclin+CDK inhibitor (Sic1). This is a checkpoint: once the inhibitor is phosphorylated, G1-cyclin+CDKs are no longer needed for entry into S-phase. SCF degrades phosphorylated Sic1.After SCF degrades Sic1 and thereby de-represses S-cyclin+CDK, S-cyclin+CDK is free to activate pre-replication complexes at the DNA origins. Active S-cyclin+CDK phosphorylates and activates proteins that initiate DNA synthesis at origins of replication. However, S-cylin+CDK is inhibited by Sic1 while S-phase cyclin and S-phase is being produced. The inhibitor is then precipitously degraded by Late-G1-Cyclin+CDK. S-cyclin+CDK is suddenly active en masse as a sudden event, rather than a slow rise in activity that would have occurred without the repressor. This permits the sudden activation of large numbers of DNA replication complexes. During the S phase, newly synthesized Cyclin B from maternal mRNA leads to formation of a new functional MPF heterodimer.
G2Cdc25 phosphatase activates mitotic-cyclin+CDK (aka MPF).
ProphaseMPF activates early mitotic events.Synthesis of mitotic cyclin leads to high MPF activity.
Spindle Assembly Checkpoint
MetaphaseMPF drives cells into metaphase.There are high levels of mitotic cyclin during metaphase, which results in high levels of MPF (mitotic-cyclin+CDK) activity.
Chromsome Segregation Checkpoint
AnaphaseAPC-Cdc20 degrades phosphorylated securin, an inhibitor bound to separase. Separase then digests cohesin's Kleisin subunit, allowing sister chromatids to separate.
TelophaseAPC-Cdh2 degrades mitotic cyclinsWhen sister chromosomes have moved apart sufficiently to ensure their complete separation into the two daughter cells, Cdc14 phosphatase activates CdcA phosphatase, which activates APC/C-Cdh2 to degrade mitotic cyclins. Thus, APC and Cdc14 phosphatase induce late steps in mitosis, telophase and cytokinesis. This results in low levels of mitotic cyclin and thus low MPF activity.
Cytokinesis