Cell Cycle Control & Cell Division pt. I & II (finished)

• Cell cycle involves DNA replication which will divide into 2 identical daughter cells
• The cell-cycle control system is what triggers the major events of the cell cycle like:

  • Ensuring cell cycle proceeds a series of 3 transitions/checkpoints to ensure each phase is complete before starting the next one
• Cell-cycle control machinery controls cell proliferation
• Cancer is uncontrolled cell proliferation
• Many genes involved in the cell-cycle regulation are critical determinants of cancer progression
• Cell-Cycle Phases:

  • Interphase: G1, S, G2
  • Mitosis: P, M, A, T
  • Cytokinesis
  • Resting Phase: G0
• Interphase:

  • G1: growth and metabolic roles
  • S: replication of DNA occurs
  • G2: growth and more preparation
• Different cell types grow at different rates
• Checkpoints in Interphase:

  • G1 Checkpoint (G1/S): checks for nutrients, growth factors, DNA damage
  • G2 Checkpoint (G2/M): checks for cell size, DNA replication
  • Metaphase Checkpoint (Metaphase to Anaphage): checks for chromosome spindle attachment
• Mitosis:

  • Prophase: chromosomes are condensed
  • Metaphase: chromosomes align at the cell center
  • Anaphase: duplicated DNA segregates
  • Telophase: chromosomes are decondensed
  • Cytokinesis: Cell splits into 2 daughter cells
• 3 Cell-Cycle Checkpoint Control System Requirements:

  1. Depends on cyclically activated cyclin-dependent protein kinases (Cdks)
  2. Depends on cyclical proteolytic events
  3. Depends on transcriptional regulation
• Cell-cycle control system ensures proper timing, order, and fidelity of events
• Cell-cycle control system responses to intracellular and extracellular signals
• Cell-cycle control system will arrest the cycle whenever the cell fails to complete essential cell-cycle process or there's unfavorable conditions
• Control by Cyclin-Cdk Complex Steps:


  • Cdk binds to cyclin
  • Undergoes phosphorylation to become an active enzyme
• Without cyclin, Cdk is inactive
• Cyclin Expression Cycle

  • G1 cyclin: cyclin D
  • G1/S cyclin: cyclin E
  • G2 cyclin: cyclin A
  • M cyclin: cyclin B
• Cyclin proteins' concentrations will oscillate throughout the cell cycle

  • Expression is induced to promote transitions through the cell cycle

  
• Concentrations of Cdk doesn't change - constitutive expression
• Appearance and disappearance fo various cyclins are critical for determining transitions from one phase to the next
• Anaphase-promoting complex or cyclosome (APC/C): initiates metaphase to anaphase transition
• During the inactive state, Cdk is blocked by a T-loop region
• When a specific cyclin binds to its cognate Cdk, the T-loop moves away from the binding site (partial activation)
• When Cdk-activating kinase (CAK) phosphorylates the T-loop which causes full activation
• Cyclin and Cdk combinations:

  • Cdk 4/6: Cyclin D
  • Cdk 2: Cyclin E
  • Cdk 2/1: Cyclin A
  • Cdk 1: Cyclin B
• Cyclin-Cdk complex is not the only prerequisite needed for regulation and the activation of downstream events
• Mutations in cyclin or Cdk can cause:

  • Cell cycle dysregulation
  • Disruption of regulatory mechanisms
  • Increase likelihood of cancer
• Activity of cyclin-Cdk is also regulated by:

  • Wee1 kinase that will keep phosphorylating Cdk to inactivate
  • Cdc25 phosphatase will dephosphorylate and restore complex activity
• Anaphase-Promoting Complex or Cyclosome (APC/C): triggers the transition from mataphase to anaphase by tagging specific proteins for degradation


  • Member of ubiquitin ligase family that control degradation of proteins by attaching ubiquitin to target proteins
• Anaphase-Promoting Complex or Cyclosome (APC/C) catalyzes ubiquitylation and degradation of securin and the S- and M-cyclins

  • Securin: protects protein linkages that hold sister chromatids together
• Securin degradation causes the activation of protease which will separate sister chromatids and start anaphase
• Degradation of S-cyclin and M-cyclin leads to inactivation of Cdk and the completion of the M phase by dephosphorylating the target
• Anaphase-Promoting Complex or Cyclosome (APC/C) is activated in mid-mitosis and remains active in G1 phase
• Cdc20 activates Anaphase-Promoting Complex or Cyclosome (APC/C)
• SCF examples:

  • Skp1
  • Cullins
  • F-box
• SCF is a ubiquitin ligase that contains 3 subunits (hence S, C, F)
• SCF ubiquitylates Cdk inhibitor (CKI) proteins in late G1

  • i.e. p27
• CKI can inhibit cyclin-Cdk complex by:

  • Binding to both cyclin and Cdk
  • Distorts active site of Cdk and p27
  • Inserts into ATP-binding site
• Cyclin gene expression fluctuates between phases and based on transcriptional levels
• Cyclin-Cdk complex is the central component of the control system and regulates transitions through different cell cycle phases