Post on 22-Jan-2016
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The Cell Cycle
• Chromosomes duplicated and segregated into two genetically identical cells
Phases Of The Cell Cycle
• S phase: DNA synthesis• M phase: nuclear and cytoplasmic division• G1, G2: gaps, monitor internal and external conditions
Morphological Changes During Cell Cycle
• In metaphase replicated chromosomes aligned at equator• At anaphase sister chromosomes move to opposite poles
Control Of Cell Cycle
• System triggers series of events in correct order
• Checkpoints: arrest cell cycle if previous events not completed or environment unfavorable
Cyclin-Dependent Kinases
• Cdks active when bound to cyclin• Cyclin-Cdk complexes promote passage through particular stages• Cyclins undergo cycles of synthesis and degradation
• Activating phosphorylation- requires activating kinase• Inhibitory phosphorylation- inhibitory kinase,
removed by phosphatase
Regulation Of Cdk Activity By Phosphorylation
Regulation Of Cdk Activity By Cdk Inhibitor Proteins
• Inhibit activity of cyclin-Cdk complex• Prevent association of Cdk with cyclin
Proteolysis of Cyclins
• Cyclin degradation by transfer of ubiquitin• Mediated by ubiquitin ligases acting at particular stages• APC/C degrades M cyclins
Initiation Of DNA Replication
• S-cyclin-Cdk phosphorylates ORC for DNA replication to begin
• Re-replication prevented by Cdc6 phosphorylation and inhibition by geminin
Early Events Of Mitosis
M-cyclin-Cdk phosphorylation of: • Nuclear lamins• Protein complex that mediates
chromosome condensation• Proteins that regulate microtubules
• Triggered by APC/C ubiquitin ligase• APC/C targets degradation of separase inhibitor,
resulting in cleavage of chromatid cohesion complex
Anaphase
Exit From Mitosis
• Chromosomes decondense, spindle disassembles, nuclear envelope reforms
• Requires degradation of M-cyclin by APC/C-mediated ubiquitylation
Control Of G1 Progression By Retinoblastoma Protein
• G1-cyclin-Cdk phosphorylates Rb, resulting in
release of E2F and transcription of S phase genes
Mitogen Stimulation
• Extracellular signals that stimulate G1- and G1/S-cyclin-Cdks
Checkpoint Mechanisms
– DNA replication checkpoint: blocks G2→M– DNA damage checkpoint: blocks G2→M
• Mediated by Cdc25 phosphatase
– DNA damage checkpoint: blocks G1→S
• Mediated by p53
• DNA damage activates p53, which turns on p21 Cdk inhibitor
DNA Damage Checkpoint by p53
Mechanics Of M Phase
• Chromosomes condense• Mitotic spindle forms
• Nuclear envelope breaks down• Chromosomes attach to spindle
microtubules
• Sister chromatids move to opposite poles
• Chromosomes aligned at equator
• Chromosomes at poles• Nuclear envelope reforms
• Contractile ring of actin and myosin pinches cell in two
• Three classes: kinetochore, overlap, astral• Participate in movement of chromosomes
Classes Of Spindle Microtubules
• Anaphase A: chromosome movement toward poles by kinetochore MT shortening
• Anaphase B: separation of poles by motor proteins and overlap MT elongation
Movement At Anaphase
Forces at Anaphase A
• Kinetochore microtubule depolymerization• Microtubule flux: prior to anaphase, tension generated
from balanced tubulin addition (+), removal (-)
• Pushing by plus end directed motors• Pulling by minus end directed motors
Motor Proteins In Anaphase B