Chapter 17 - Cell Cycle

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Created by
Natalie Gifford

Cards (20)

  • Cell Cycle - general
    1. Interphase - G1, S Phase (DNA replication), G2
    2. M Phase - mitosis (nuclear division), cytokinesis (cytoplasmic division)
    3. G0
  • Cyclins/cdks govern process through cell cycle
  • Cdks - have kinase activity and are only active when bound to cyclin
  • Cyclins - transcriptionally activated and Ubiquitin based degradation
  • G1-cdk: Cyclin D and cdk 4
  • G1/S cdk: Cyclin E and cdk 2
  • S-cdk: Cyclin A and cdk 2
  • M-cdk: MFP - Cyclin B and cdk1 (aka cdc2)
  • G0 to S Phase
    1. EC signal binds to receptor - mitogen
    2. Activation of Ras - Monomeric GTPase
    3. Activation of MAPK pathway
    4. Phosphorylation of c-myc (activation)
    5. Increase transcription/activation of Cyclin D, Ubiquitin ligase component, E2F
    6. Accumulation of Cyclin D activated G1-cdk
    7. G1-cdk increases transcription of cyclins E and A
    8. Rb binds to E2F
    9. G1-cdk phosphorylates Rb
    10. P-Rb released
    11. E2F stimulates transcription of cyclins E and A - G1/S-cdk and S-cdk
    12. S-cdk held inactive by p27 interaction
    13. G1/S-cdk phosphorylates p27
    14. p27 targeted for ubiquitin degradation
    15. S-cdk is active - S phase begins
  • S Phase
    1. Active S-cdk phosphorylates proteins in Origin recognition complex (ORC)
    2. ORC bind ORI - acts as docking site for other proteins
    3. cdc6 levels increase in G1 and bind to ORC - required for mcm binding
    4. mcm proteins (helicases) bind to ORC
    5. DNA replication is initiated
    6. S-cdk prevents re-replication by phosphorylating cdc6 (for ubiquitin mediated degradation) and phosphorylating mcm (causes export to the cytoplasm)
  • G2 to M Phase
    1. M-cdk (cyclin B and cdk-1- MPF)
    2. Cyclin B is synthesized in S and G2
    3. M-cdk held inactive until needed in M phase
    4. Wee-1 phosphorylates M-cdk on 2 sites (Thr-14, Tyr-15)
    5. End of G2- a lot of M-cdk but it is inactive
    6. Late in G2- POLO kinases activate cdc25
    7. cdc25 (active) removes phosphates on M-cdk (put on by Wee-1)
    8. CAK activates M-cdk by phosphorylating cdk-1 of M-cdk (Thr-161)
    9. Early M Phase Regulation
    10. Anaphase - M Phase Regulation
  • G2 to M Phase - Early M Phase Regulation
    1. M-cdk is active and important for:
    2. Actin cytoskeletal reorganization - cell rounded
    3. Chromatin condensation - Phosphorylation of condensin complex
    4. Spindle assembly
    5. Chromosome alignment on metaphase plate
    6. Nuclear envelope breakdown
    7. Lamins A, B and C - intermediate filaments
    8. M-cdk phosphorylates lamins
    9. Depolymerization of intermediate filaments
  • G2 to M Phase - Anaphase- M Phase Regulation
    1. M-cdk activates APC (complex with cdc20 for activation)
    2. APC directs ubiquitin mediated degradation of anaphase inhibitor
    3. Sister chromatids held together by cohesion complex
    4. Before anaphase - securin binds/inhibits activation of separase
    5. APC causes ubiquitin degradation of securin at end of metaphase
    6. Separase cleaves component of cohesion complex
    7. Sister chromatids separate - anaphase begins
    8. APC directs ubiquitin degradation of M-cdk cyclins
    9. M-cdk no longer -Ps proteins in M phase events
    10. Nulcear envelope re-forms etc.
    11. Cells enter G0 or G1 again
  • G1 Checkpoint - Looks for DNA damage before S phase
  • G1 Checkpoint - Undamaged DNA
    1. p53 is unstable/present at low concentrations
    2. p53 interacts with mdm2
    3. Activates ubiquitin ligase - degrades p53
    4. DNA synthesis occurs
  • G1 Checkpoint - Damaged DNA
    1. Activates a kinase (ATM/ATR) that phosphorylates p53
    2. Decreases affinity for mdm2
    3. p53 enhances transcriptions of p21
    4. p21 binds G1-cdk and G1/S-cdk and inhibits activation
    5. DNA synthesis inhibited
  • G2 Checkpoint
    • Entry into M phase is halted if not replicated appropriately
    • Every nt has to be replicated to enter into M phase
  • G2 Checkpoint - Late in G2
    1. Damaged DNA sends a signal to a protein kinase (Chk-1)
    2. Chk-1 phosphorylates cdc25 (inhibits)
    3. This blocks de-phosphorylation of M-cdk
    4. M phase is blocked
  • M Phase Checkpoint - Spindle attachment checkpoint
    • Ensures all chromosomes are properly attached to spindles
    • Mechanisms that monitor state of kinetochores
  • M Phase Checkpoint - Kinetochore not attached to spindle will:
    1. Send a signal to cell cycle and blocks APC activation
    2. Mad2 is recruited to unattached kinetochores
    3. Inhibits APC activation by cdc20
    4. Inhibits securin destruction
    5. Sister chromatids don't separate - until all kinetochores attached