Download The Cell Cycle

The Cell Cycle
Overview of Cell Cycle Events
Mutants that Arrest the Cell Cycle
S. pombe Cell Cycle Mutants
Wee1 & Cdc25
• wee1 kinase
– inhibits Cdk1-cyclinB in G2
– mutation allows progression into
mitosis without growth
• Cdc25 phosphatase
– promotes G1 S transition
– mutation prevents DNA
replication and mitosis
Cell Cycle Progression Regulated
by Cdks and Cyclins
Regulation Run Amok
• 18.1-Cdk2.mov
Cdk-Cyclin Activities During the Cell
Cycle
G1-S Restriction Point
Regulation of
Transcription of
Key Cell Cycle
Progression
Genes by Rb &
E2F during G1
External Signals Ultimately Trigger
Phosphorylation of Rb
Aberrations in Cell Cycle Control
Proteins Lead to Cancer
G1-S Transition
• Cdk4/6-cycD
– P-pRb
– PpRb releases E2F
– E2F txbs CycsA & E
– Cdk2-cycE spike
triggers S-phase
G1-S Checkpoint And S-Phase
Considerations
• Replication should not begin if DNA is
damaged
• DNA integrity monitored by
– p53 induced genes
• The p53 conundrum
– too little – bad
– too much - bad
p53 & Mdm2 in G1-S Checkpoint
• Mdm2
– Ubiquination of p53
– Maintains level of p53
• p53
– P’ated in response to
damaged/unreplicated
DNA
– Mdm2 doesn’t bind
P’ated p53
• P-p53 activates
apoptosis
S-Phase Controls
• Replication must occur only 1 time / cell cycle
• Origin “licensing”
• ORC – origin
recognition
complex
• SPF – S-phase
promoting
factor
• Mcms
– helicases that are
only loaded once
Regulation by Phosphorylation
• CAKs P’ate T161 of T loop to activate
• Wee1/Myt1/Mik1
P’ate T14 & Y15
to inactivate
• Cdc25 deP’ates
T14 & Y15 to
activate
Nuclear Localization of Cdk1-cycB1 Occurs at
G2/M Transition
• Cdk1 cytoplasmic , cyclinB1 shuttles, Cdk1-cycB1 shuttles
• At end of G2 P’tion of CycB1nuclear export signal when
complexed to Cdk1
– CycB1 carries Cdk1 into nucleus
– Cdk1-cycB1 then trapped within nucleus
– Activated by deP’tion of T14 & Y15 by Cdc25
Activation of Cdk1-cyclin Requires
Inactivation of Cdk2-cyclinA
G2 Checkpoint
• Is DNA replication complete
• Is DNA undamaged