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Cell Cycle

Cell Cycle. Sequential series of events from one mitosis to the next Regulated at critical transition points: G1/S and G2/M Regulation is essential for growth control and for genetic integrity. Cell Cycle - Overview. The G2/M Transition. Occurs when cell cycle events are “complete”

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Cell Cycle

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  1. Cell Cycle • Sequential series of events from one mitosis to the next • Regulated at critical transition points: G1/S and G2/M • Regulation is essential for growth control and for genetic integrity

  2. Cell Cycle - Overview

  3. The G2/M Transition • Occurs when cell cycle events are “complete” • Requires intact genome, replicated chromosomes, accumulation of critical factors mediating exit from interphase - prophase and entry to M phase. • MPF (“metaphase-promoting factor,” a.k.a., “mitosis-promoting factor,” a.k.a. “maturation-promoting factor”) is universal regulator of this important transition

  4. End-point of G2/M = Metaphase

  5. How do we know that MPF is essential? • Xenopus oocyte “meiotic maturation” - a model system • MPF in other cells • M-phase regulation revealed by yeast mutants • Saccharomyces cerevisiae - CDC28 • Schizosaccharomyces pombe - cdc2 • “Intersecting cell cycles” - topic for journal critique, Tuesday 16 April

  6. Xenopus - Meiotic Maturation

  7. MPF Activity Cycles

  8. Further Evidence for Universal “MPF”

  9. Budding Yeast Cell Division Cycle (cdc) Mutants

  10. Fission Yeast cdc Mutants

  11. Evidence for “Cyclin” Activity • Sea urchin (yet another model!): a specific protein cycles in quantity during cleavage divisions of the embryo • This was designated “cyclin” • Subsequently, it was shown that this protein co-purifies with MPF activity, but that it is not the sole component of MPF • MPF = cyclin B + p34 (CDC28/cdc2)

  12. Phosphorylation and Dephosphorylation Regulate MPF Activity • Y15 - inhibitory phosphorylation by wee1/mik1 kinases • Active site for ATP binding • T161 - phosphorylated by Cdk7/CycH (CAK) • This residue occludes substrate-binding site until it is phosphorylated • Y15 - active dephosphorylation by Cdc25 protein phophatase

  13. Kinases and Phosphatases

  14. Missing Pieces: MPF/Cdk Substrates • Dramatic increase in phosphorylated proteins - MPM2 antigens • Autophosphorylation of cdc2 • *Histone H1 phosphorylation assay (physiological significance?) • Histone H3 phosphorylation on ser10 may be more significant • Spatially and temporally correlated with chromosome condensation • Nuclear lamins - phosphorylation leads to solubilization (breakdown of nuclear envelope)

  15. How do cells get out of metaphase? • Via anaphase by action of the anaphase promoting complex (APC) • Injection into Xenopus oocytes of RNA encoding non-degradable cyclin B leads to sustained high MPF and metaphase arrest • Ubiquitination of chromosome cohesins and cyclin targets them to the proteosome

  16. Synthesis - Destruction Cycle

  17. Other Cell Cycle Kinases • MPF - Cdk1 = “maestro of M phase • NIMA (“never in mitosis”) family of kinases (Aspergillus nidulans) • Polo family kinases (Drosophila melanogaster) • Aurora family kinases • All implicated in control of centrosome and spindle poles

  18. Multiple Cdk-Cyclin Complexes Regulate Cell-Cycle Transitions • G1 inactivation of APC • G1/S • G2/M

  19. Models for Cdk Regulation

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