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22 Mar 2011
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LECTURE March 22, 2011
Cell cycle and programmed cell death
Cell divides into two identical daughter cells
Need to segregate components equally between the daughter cells
oPrecisely
oMany control mechanisms are to ensure precisely equal distribution of
chromosomes
oMany cancers have wrong number or pieces of chromosome
oESSENTIAL STEP
G1 = gap phase number 1
oLiving and growing and duplicating its mitochdonria
oGrowing in size
S phase
oSynthesizes DNA chromosomes replicate
G2 phase
oContinues growing until double in size
oDoubled everything
Mitosis
oNuclear division followed by cytosolic division
oEnd with two equivalent daughter cells
Steps must be in order and controlled
oQuestions and answers come in molecular switches molecules
phosphorylated, ubinquinated, etc.
oDecisions made at special times in cycle called cell cycle checkpoints
S-phase once enter S-phase, its committed can pause but must
divide, otherwise undergo programmed cell death
At any point, cell can wait or go
Cyclin-dependent kinase phosphorylates
Only active when in complex with cyclin
Portrayed on slide is the active form of complex
Regulated by which cyclin it interacts with
Are protein kinases
Different cyclin-Cdk checkpoints at at different stages of
the cell cycle
oDifferent cyclin at M step and S step
S-cyclin transcribed and translated cell indicating its
ready to enter S phase
M-cyclin phosphorylates things for mitosis
Then degraded
Table describing different cdk complexes
Cylin d with cdk4 will drive past g1-cdk point
Cdk2 involved in two different checkpoints a combinatorial effect
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oCdk2 a protein that phosphorylates what it phosphorylates
depends on the partner at the time
oDifferent target depending on partner
oIn YEAST, only CDK1 cyclins swapped combinatorial effect
oLike in integrin adhesion sticking to lamina alpha 6 and beta 5
versus alpha 4 and beta 6
oIgnore asterisks
CDK has T-loop in red
Part of its polypeptide chain
In inactive state Tloop in active site of enzyme cannot phosphorylate
targets
Cyclin binds, pulling T-look out but not completely partial activation
Enzyme CDK activating kinase adds activating phosphate to fully activate
Once activated, certain targets
oS-cdk complex activity promotes DNA replication
oInhibits inhibitor positive so DNA replicates
oRequired to start mitosis
Phosphorylates multiple targets
Lamin part of nuclear membrane so it falls apart
Interphase to mitosis kind of cytoskeleton
Actual machinery that causes cell to change shape or
function or divide
Transcription and translation of cyclin makes it available
Protein degradation makes it unavailable
Targeted degradation of cyclins turns Cdks off
To destroy protein, polyubinquainate it so it can be recognized for
degradation
Active APC/C recruits set of ubiqinating enzymes
M-cyclin can be recognized by protesome so can be garbaged
M-cyclin is gone
Necessary to destroy m-cyclin to lallow mitosis to finish
oSo the destruction must occur during mitosis
More control needed
Cdk Inhibitor proteins
oP27 binds to cyclin cdk complex
oP27 blocks active site of cdk
oSo cdk inactivated
oTwo separate steps to activate this cell cycle checkpoint
Activate cdk cyclin complex
Activate p17-cyclin-cdk complex
Two independent controls coming to a decision both must
fail to fail
Phosphorylation
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Document Summary

 cell divides into two identical daughter cells.  need to segregate components equally between the daughter cells: precisely, many control mechanisms are to ensure precisely equal distribution of chromosomes, many cancers have wrong number or pieces of chromosome, essential step.  g1 = gap phase number 1: living and growing and duplicating its mitochdonria, growing in size.  s phase: synthesizes dna chromosomes replicate.  g2 phase: continues growing until double in size, doubled everything.  mitosis: nuclear division followed by cytosolic division, end with two equivalent daughter cells.  steps must be in order and controlled: questions and answers come in molecular switches molecules phosphorylated, ubinquinated, etc, decisions made at special times in cycle called cell cycle checkpoints.  s-phase once enter s-phase, it"s committed can pause but must divide, otherwise undergo programmed cell death.  at any point, cell can wait or go.  cylin d with cdk4 will drive past g1-cdk point.

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