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Cyclins and cyclin-dependent kinases (Cdks) are regulatory proteins that control cell division. While Cdk levels remain constant, cyclin concentrations fluctuate during different cell cycle phases. When cyclins bind to Cdks, they become phosphorylated and activated, driving the cell through specific phases. This dynamic regulation ensures orderly progression through the cell cycle.

The M-phase promoting factor (MPF) forms when cyclin B binds to Cdk1 as the cell approaches the M phase. Wee1 kinase initially keeps MPF inactive by phosphorylating tyrosine residues. Cdc25 phosphatase then dephosphorylates MPF, and a Cdk-activating kinase phosphorylates a threonine residue, fully activating MPF and triggering mitosis.

External factors significantly influence cell division initiation. Growth factors and human growth hormone (hGH) promote cell division, while their absence inhibits it. Cell crowding also suppresses division, and the death of nearby cells can stimulate division. These external chemical stimuli work alongside internal regulators to control when cells divide.

Negative regulators including p53 and p21 halt cell cycle progression. When p53 detects DNA damage, it recruits repair enzymes and triggers apoptosis if damage persists. Elevated p53 levels stimulate p21 synthesis, which binds to Cdk/cyclin complexes and blocks progression to the S phase, preventing damaged cells from dividing.

Cyclin concentrations vary predictably across cell cycle phases. Cyclin D rises in G1 and remains high through most phases. Cyclin E peaks at the G1-S junction, while cyclin A is elevated during S and G2 phases. Cyclin B levels rise as the cell approaches M phase, promoting the transition to mitosis.

The retinoblastoma protein (Rb) functions as a negative regulator that halts the cell cycle. It prevents cells from progressing through critical checkpoints until appropriate conditions are met. By blocking cycle progression, Rb ensures that cells complete each phase properly before advancing, maintaining genomic stability.

Phosphorylation and dephosphorylation events precisely regulate MPF activity. Wee1 kinase phosphorylates tyrosine residues on MPF to keep it inactive and prevent G2/M transition. Cdc25 phosphatase reverses this by dephosphorylating MPF, allowing a Cdk-activating kinase to phosphorylate threonine and fully activate MPF for mitosis.