cell cycle sequential series of events from one mitosis to the next regulated at critical transition...
TRANSCRIPT
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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 APCG1/SG2/M
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Models for Cdk Regulation