(L3) The cell cycle 2

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Cdk activity is controlled by what?
Concentration of cyclins (synthesis and degradation), Phosphorylation and dephospho rylation of Cdk itself and Cdk inhibitor proteins which bind to cyclin-Cdk complexes to inhibit activity
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Name the 3 major control points in the cell cycle
1) G1 to S transition (G1-Cdk, G1/S-Cdk and S-Cdk), 2) Entry to mitosis (M-Cdk), 3) Transition to anaphase (M-Cdk)
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Describe the G1 to S transition
At the start, no cyclins present. G1-cyclin accumulates & binds to Cdk, activating G1/S and S cyclin gene transcription, G1/S C binds to Cdk and increases S-Cdk activity, then S-Cdk promotes DNA synthesis
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Name 3 ways that G1/S-Cdk increases the activity in the S-Cdk
1) Activates transcription of S-cyclin genes (^S-cyclin synthase), 2) Inhibits an S-Cdk ubiquitin ligase (decrease Cdk degradation), 3) Inhibits an S-Cdk inhibitor protein (catalytic activity of s-Cdk increases as this activates S-Cdk)
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What do all of the steps of the G1 to S transition include?
Phosphorylation of target proteins
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What signals tend control growth?
External signals (small molecules)
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Give examples of external signals in animals?
Mitogens stimulate cell division, growth factors cause the cell to increase in mass
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Give 2 examples of proteins that stimulate both cell division and increase in mass
1) Platelet-derrived growth factor, stimulates many kinds of cell to divide and grow, 2) Erythropoietin, includes proliferation of red blood cell precursors
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Why does erythropoietin only proliferate RBC precursors and not RBC?
Because RBC can't proliferate (divide) as they have no nucleus
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Describe what mitogens do in order to trigger cell division
Binds to cell surface and indirectly increases cyclin activity, an important mechanism in stimulating G1-cyclin gene transcription so more G1 accumulates
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Where is one of the principle actions of G1-Cdk?
On the Rb protein
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What is retinoblastoma?
Inherited eye cancer in children, caused by the loss of both copies of the RB1 gene which codes for the Rb protein (Rb is not specific to the eyes however)
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What does cancer involve?
Activation of cell division
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In normal cells, what does the Rb protein do?
Prevents premature cell division by blocking the transition to S phase, it inhibits the transcription of the G1/S-cyclin and the S-cyclin genes by binding to transcription factor E2F
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How does the Rb protein become inactivated and why?
G1 phosphorylates it so that E2F can be released and G1/S-cyclin and S-cyclin genes start to be transcribed, triggering the G1 to S transition
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Once G1/S-Cdk and S-Cdk starts to accumulate, what happens?
They also inactivate RB1 protein
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What happens to E2F?
It stimulates its own transcription (positive feedback)
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When should DNA not be replicated?
When it is damaged
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In animals, what is the key protein in controlling response to DNA damage?
p53
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What happens when DNA is damaged?
p53 accumulates, increasing the usually low levels, damaged DNA leads to phosphorylated p53 (preventing binding of ubiquitin), p53 activates transcription of p21, which is a Cdk inhibitor protein & inhibits G1/S-Cdk and S-Cdk
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What does inhibiting G1/S-Cdk and S-Cdk do?
Allows time for the DNA to be repaired
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When does synthesis of M-cyclin start?
During G2 phase (M0cyclin binds to Cdk to form M-Cdk)
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What happens to the M-Cdk when its accumulated?
Wee1 kinase phosphorylates it to inhibit the Cdk activity
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When and how is M-Cdk activated?
In late G2, Cdc25 phosphatase is activated by phosphorylation and in turn this dephosphorylates M-Cdk, so it activates it once again
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What is Cdc25 phosphatase activated by?
It is phosphorylated by a polo-like kinase
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What are polo-like kinases?
Widespread in eukaryotes, activity of polo-like kinases increases during G2 and M phases, the mechanism of polo kinase activation is not fully understood but it depends on S-Cdk
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What happens when M-Cdk is activated?
It activates Cdc25 phosphatase and inhibits wee1 kinase (Positive feedback)
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What does full activation of cyclin-Cdk require?
Phosphorylation by Cdk-activating kinase at the active site
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How does this differ from inhibitory phosphorylation by Wee1 kinase?
They are 2 separate phosphorylation processes with opposite effects
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What is the consequence of incomplete replication or DNA damage?
Cdc25 phosphatase does not dephosphorylate M-Cdk, it is not know how incomplete replication or DNA damage are sensed
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Other cards in this set

Card 2

Front

Name the 3 major control points in the cell cycle

Back

1) G1 to S transition (G1-Cdk, G1/S-Cdk and S-Cdk), 2) Entry to mitosis (M-Cdk), 3) Transition to anaphase (M-Cdk)

Card 3

Front

Describe the G1 to S transition

Back

Preview of the front of card 3

Card 4

Front

Name 3 ways that G1/S-Cdk increases the activity in the S-Cdk

Back

Preview of the front of card 4

Card 5

Front

What do all of the steps of the G1 to S transition include?

Back

Preview of the front of card 5
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