Lecture 23 Regulation of the Cell Cycle

Lecture 23 Regulation of the Cell Cycle - IPHY 3060 Lecture...

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IPHY 3060 Lecture 23: Regulation of the Cell Cycle
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Progression through the Cell Cycle is Associated with Changes in Cyclin/CDK Activity
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CDKs are activated 5 ways: Increased expression of cyclins and CDKs at the start of each phase Binding of CDK to cyclin Phosphorylation of cyclin/CDK complex Decreased expression of CIPs and KIPs Inactivation of CIPs and KIPs by phosphorylation
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CIPs and KIPs Bind to and inactivate cyclin/CDKs Their binding to cyclins/CDKs can be inhibited by phosphorylation Cyclin CDK p21CIP When cell is not dividing, cyclin/CDKs levels are low, they are not phosphorylated, and they are bound to CIPs and KIPs, which are at high levels and also unphosphorylated
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Entry into G 1 from G 0
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Entry into Cell Cycle Is Controlled By Growth factor- mediated increased expression of early G 1 cyclin/CDKs Growth factor- mediated decreased expression of CIPs and KIPs Growth Factors Early G 1 cyclin/CDK expression CIP and KIP expression Increased Cell Proliferation
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3 Major functions of early G 1 phase cyclin/CDKs: Regulate the activity of proteins associated with cell growth in G 1 Activate expression of late G 1 /S phase cyclin/ CDKs Start the expression of DNA synthesis initiation factors
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Restriction Point: The point in late G 1 phase at which cells become committed to enter the S phase and complete the cell cycle The point at which early G 1 cyclin/CDKs have produced enough expression of late G 1 and S phase cyclins that further input from growth factors is not necessary
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Increased transcription of late G 1 and S phase cyclins depends on E2F transcription factors Late G 1 and S phase cylin and CDK genes Cyclin A/E CDK2
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Cyclin D and Passage Through the Restriction Point Step 1: The E2F transcription factors are normally bound to the protein Rb
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Cyclin D and Passage Through the Restriction Point Step 2: Early G 1 phase cylin/CDKs phosphorylates Rb In early G 1 phase
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Cyclin D and Passage Through the Restriction Point Step 3: Phosphorylation of Rb causes it to dissociate from E2F
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Cyclin D and Passage Through the Restriction Point Step 4: E2F activates expression of genes involved in DNA synthesis, including late G 1 and S phase cyclin/CDKs
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Cyclin D and Passage Through the Restriction Point Step 4: E2F activates expression of genes involved in DNA synthesis, including late G 1 and S phase cyclin/CDKs
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Cyclin D and Passage Through the Restriction Point Step 4: E2F activates expression of genes involved in DNA synthesis, including late G 1 and S phase cyclin/CDKs DNA Synthesis Factors
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Cyclin D and Passage Through the Restriction Point Step 5: Late G 1 phase cylin/CDKs continue to phosphorylate Rb in late G 1 , further increasing activity of E2F and expression of DNA synthesis genes DNA Synthesis Factors
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G 1 to S Phase Transition
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G 1 to S phase transition Cyclin A CDK2 Step 1: E2F activates expression of S phase cyclin/CDKs
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G 1 to S phase transition Cyclin A CDK2 Step 1: E2F activates expression of S phase cyclin/CDKs p21CIP Step 2: p21CIP binds to and inactivates S phase cyclins
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Lecture 23 Regulation of the Cell Cycle - IPHY 3060 Lecture...

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