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#MPF

3 public questions tagged with this topic.

Cell Cycle Regulation

The M-phase regulator known as MPF (Maturation Promoting Factor) consists of:

Experiments in amphibian oocytes and in yeast genetics converged upon identification of universal M-phase regulator historically called Maturation Promoting Factor for its ability to induce meiotic maturation when cytoplasm from M-phase cells injected into G2 oocytes. Molecular composition resolved as complex of catalytic subunit CDK1 originally named cdc2 or p34cdc2 and regulatory subunit Cyclin B. CDK1 provides serine-threonine kinase activity requiring activating phosphorylation on activation loop Thr161 by CAK complex CDK7-Cyclin H-MAT1 and removal of inhibitory phosphates Thr14 Tyr15 via Cdc25 phosphatase. Cyclin B synthesized during S and G2 accumulates at G2/M, contains destruction box recognized by APC/C-Cdc20 for degradation providing temporal restriction, supplies cyclin box for CDK activation and contributes substrate docking through hydrophobic patch recognizing RXL motifs plus nuclear localization signal translocating complex into nucleus at prophase. MPF substrates include lamins causing envelope breakdown, condensin subunits driving chromosome compaction, microtubule regulators forming bipolar spindle and APC/C components regulating exit. Degradation of Cyclin B at anaphase inactivates MPF, allowing phosphatases to restore interphase state.

Ref: Nurse, Universal Control of Cell Division by CDK1-Cyclin B MPF, Nature 1990; Alberts et al., Molecular Biology of the Cell, Chapter 17, Discovery of MPF.

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Cell Cycle Regulation

The mitotic CDK1-Cyclin B complex (MPF) is responsible for:

MPF converts interphase architecture into mitotic state through phosphorylation of hundreds of substrates. Nuclear entry of CDK1-Cyclin B, facilitated by phosphorylation of Cyclin B cytoplasmic retention sequence, allows access to chromatin proteins. Condensin I and II pentameric complexes containing SMC2, SMC4 become phosphorylated at non-SMC subunits CAP-D2, D3, CAP-G, H2, activating ATP-dependent loop extrusion that folds 10nm fiber into 700 nm wide rod chromosomes. Lamins phosphorylated at Ser22 Ser392 disassemble intermediate filament meshwork leading to nuclear envelope breakdown and merging with endoplasmic reticulum. Golgi matrix proteins GRASP65 GM130 phosphorylated causing vesiculation and partitioning. Interphase microtubule array destabilized while centrosomal gamma-TuRC recruitment of pericentrin enhanced drives bipolar spindle formation after Eg5 kinesin activation and NuMA dynein redistribution. Transcription inhibition through TFIIH and TFIID phosphorylation silences gene expression. Together these modifications reconfigure cell for chromosome capture, alignment and segregation, all attributable to single CDK1-Cyclin B holoenzyme activity rising at mitotic onset and falling after anaphase due to cyclin B destruction. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.

Ref: Hirano, Condensins and Mitotic Chromosome Architecture, Nat Rev Mol Cell Biol 2012; Alberts et al., Chapter 17, MPF Targets.

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Cell Cycle Regulation

Which complex regulates the G2/M transition?

G2 to M transition represents bistable switch controlled by accumulation of active CDK1-Cyclin B, often termed mitosis-promoting factor. Throughout G2, Cyclin B synthesis steadily rises transcribed by FoxM1 and stabilized, yet associated CDK1 remains inactive due to inhibitory phosphorylations at Thr14 and Tyr15 catalyzed by nuclear Wee1 and cytoplasmic Myt1 kinases occupying ATP-binding pocket. At threshold, dual specificity phosphatase Cdc25B initially and subsequently Cdc25C removes these phosphates. Activating Thr161 phosphorylation by CAK complex CDK7-Cyclin H further boosts activity. Once small amount of CDK1-Cyclin B activates, it initiates powerful feedback circuits: phosphorylation and activation of Cdc25 isoforms generating positive feedback, and phosphorylation and inhibition of Wee1 plus degradation via SCF-betaTrCP producing double negative loop. Rapid autoamplification creates abrupt switch. Active CDK1-Cyclin B translocates into nucleus via importin beta and cyclin B nuclear localization signal phosphorylation, phosphorylating lamins, condensins, Golgi and microtubule motors orchestrating prophase. DNA damage checkpoint via ATR-Chk1 inhibits Cdc25 and stabilizes Wee1 to maintain G2 arrest. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.

Ref: Morgan, Cell Cycle Control Principles of G2/M Transition, Chapter 3; Alberts et al., Molecular Biology of the Cell, CDK1-Cyclin B Regulation.

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