Cell Division & Cycle Control

• Mitosis results in cell reorganization preceded by DNA, organelle replication, and protein synthesis for cell division.
• The cell cycle control system, a network of regulatory proteins, accomplishes the entire division process.
• It controls protein machineries involved, switching them on/off at the correct time.
• The system activates proteins for each specific process and inactivates them once completed.
• It ensures each phase is completed before the next and ensures correct progression through the cycle.
• The cell-cycle control is based on cyclically activated protein kinases.
• Kinases phosphorylate and activate multiple proteins for DNA replication, mitosis, and cytokinesis.
• Kinases are present throughout the cycle but activated only at appropriate times, then rapidly become inactive.
• Phosphorylation of cell-cycle protein machineries is reversed by protein phosphatases.
• The kinase concentration is constant during the cycle, but activation is time-specific, followed by rapid inactivation.
• Kinase activity rises and falls cyclically.
• Cyclins bind to cell-cycle kinases for activation and these kinases are known as cyclin-dependent protein kinases(Cdks).
• Unlike Cdks, cyclin concentrations vary cyclically during the cell cycle.
• Periodic synthesis and degradation of cyclins switch the cell-cycle kinase activity on and off.
• Even when cyclin B and Cdk are present in other stages, the cyclin and kinase complex is regulated further by phosphorylation-dephosphorylation.

Cyclin B synthesis in S phase

• Cyclin B accumulates and forms complexes with the M phase Cdk throughout S and G2 phases.
• M phase Cdk is still enzymatically inactive despite associating with cyclin B.
• As the cyclin B-Cdk complex forms, the M-phase Cdk is phosphorylated by an activating kinase and an inhibitory kinase.
• Activating kinase is at the site for activity.
• Inhibitory kinase overrides the activating kinase and inhibits activity.
• The cyclin B-Cdk complex remains inactive at this stage.
• At the end of interphase (G2 phase), the M phase Cdk is activated by a specific protein phosphatase called Cdc25.
• Cdc25 removes the inhibitory phosphate group, leaving the activating phosphates.
• Once activated, the M phase Cdk phosphorylates and activates a variety of target proteins during mitosis in the M phase.
• Cdc25 is a target whose phosphorylation further activates the phosphatase activity, producing a positive feedback loop and activated cyclin B-M phase Cdk further activates itself.
• Toward the end of mitosis, the M phase Cdk is inactivated by proteolytic degradation of cyclin B, leading the cell to exit mitosis and undergo cytokinesis, and return to interphase (G1 phase).
• Toward the end of G1 phase, the inactivated M phase Cdk is dephosphorylated by a specific protein phosphatase.
• The inactive, unphosphorylated M phase Cdk kinase is ready to form a complex with cyclin B.

Targets of cyclin B-M phase Cdk complex

• Chromatin condensation targets phosphorylated condensins.
• Mitotic spindle formation targets microtubule-associated proteins.
• Nuclear envelope breakdown targets lamins.
• By phosphorylating and activating key target proteins required during mitosis, the cyclin B - M phase Cdk complex induces multiple nuclear and cytoplasmic changes leading to a major reorganization of the entire structure of the cell during M phase.
• During prophase, condensin is activated by cyclin B-M Cdk-mediated kinase activity; it participates in chromatin condensation, leading to visible M-phase chromosomes.
• Phosphorylation of microtubule-associated proteins during prophase promotes their ability to cross-link microtubules that grow from opposite spindle pole poles leading to mitotic spindle formation.
• During prometaphase, the phosphorylation of lamins triggers the disassembly of the nuclear lamina breaking the nuclear membrane into vesicles.

Major Cyclins and Cdks in Vertebrates

• G1-Cdk has cyclin D and Cdk4/6.
• G1/S-Cdk has cyclin E and Cdk2.
• S-Cdk has cyclin A and Cdk2.
• M-Cdk has cyclin B and Cdk1.