unregulated cell cycle.txt

  1. Unregulated cell cycle causes
    Mutations in 3 main checkpoints can lead to de-regulated cycling >> lead to disease
  2. S to G2 checkpoint
    • Protein important in controlling replication and repair
    • These are PIKK related kinases, including…
    • ATR (focus of studying)
    • ATM
    • DNA-PK
  3. Role of ATR
    • Essential in replicating of mammalian cells
    • In S Phase: aids in initiation of replication, stability of replisome and replication fork restart
    • In G2: (focus of study) prevents premature mitotic entry in presence of DAMAGED DNA
    • Fxns as UPSTREAM regulator of p53 phosphorylation
  4. Role of p53
    • Tumor suppressor protein
    • Protects against propagation of cells that have DNA damage w/ potential oncogene mutations
    • Phosphorylation of p53 = release from MDM-2
  5. Role of MDM2
    • Suppressive function: Limits p53 growth in unstressed cells
    • Monoubiquitinates p53 >> leading to its degradation
  6. p53 MDM-2 binding
    • bound in both their amino-terminal domains
    • p53 resides in hydrophobic pocket of MDM-2 amino terminal where it is BLOCKED from transcription machinery
  7. Consequence of NO p53 phosphorylation
    • Possibly from MUTATION in ATR
    • Can lead to unregulated cell growth of NON-VIABLE cells, as G2 >> M checkpoint is lost
    • Seckel Syndrome can result >>> severe dwarphism, mental retardation, uncontrolled cell proliferation
  8. Role of extra centrosomes in chromosome instability
    • Caused by multipolar spindle formation, which promotes MEROTELY
    • Centrosomes CLUSTER at 2 poles
    • Bipolar Anaphase occurs w/chromosome lagging
    • Cohesion defects
    • Mitotic checkpoint defects
  9. Result of extra centromeres in chromosome
    ASSYMETRIC chromosome segregation >> results in severe Aneuploidy
  10. Merotely
    • Kinetichores attach to SPINDLE tubules from DIFFERENT poles, causing:
    • Chromosome lagging
    • Chromosome damage
    • Missegregation and aneuploidy
  11. Causes of extra centromeres
    • Centriole duplification, caused by VIRAL infection OR Overexpression of:
    • 1. PLK4 or
    • 2. Aurora A Kinase
  12. PLK4
    • Required for centriole duplification
    • 26S proteasome degrade this…so by INHIBITING this, you have centriole overduplification
  13. Multipolar mitosis
    • Rare occurances
    • Cells that divide through this have LOW VIABILITY
  14. Chromosome instability definitions
    • Increased rate of chromosome missegregation during cell division
    • Gain (or Loss) of chromosome: Aneuploidy
    • Failure to maintain correct chrom. Complement: euploidy
Card Set
unregulated cell cycle.txt
unreg cell cycle