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Published byStuart Sutton Modified over 9 years ago
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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
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Cell Cycle - Overview
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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
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End-point of G2/M = Metaphase
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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
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Xenopus - Meiotic Maturation
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MPF Activity Cycles
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Further Evidence for Universal “MPF”
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Budding Yeast Cell Division Cycle (cdc) Mutants
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Fission Yeast cdc Mutants
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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)
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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
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Kinases and Phosphatases
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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)
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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
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Synthesis - Destruction Cycle
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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
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Multiple Cdk-Cyclin Complexes Regulate Cell-Cycle Transitions G1 inactivation of APC G1/S G2/M
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Models for Cdk Regulation
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