BA

Cell Cycle Regulation for Exam 3

Cell Cycle Regulation

Molecular Switches

  • The cell cycle is controlled by molecular switches.
  • These switches are proteins that dictate whether the cell cycle moves forward or stops.
  • Two important types of enzymes:
    • Protein kinases
    • Protein phosphatases

Protein Kinases

  • Responsible for phosphorylating proteins.
  • Transfer phosphate groups.
  • Enzymes that phosphorylate proteins.

Protein Phosphatases

  • Dephosphorylate proteins.
  • Remove phosphate groups.

Key Proteins

  • Cyclins
  • Cyclin-dependent kinases (Cdks)
  • These control other proteins.

Cyclins

  • Made when needed due to hormonal signaling.
  • Often considered oncogenes or proto-oncogenes.
  • Act as the "gas pedal" of the cell cycle.
  • Stimulate cell division.

Cyclin-Dependent Kinases (Cdks)

  • Always present inside the cell.
  • When combined with cyclins, act as a protein kinase.
  • Cause phosphorylation of other proteins.

Cyclin and Cdk Combinations

  • Work together at different phases of the cell cycle:
    • G1 to S transition
    • S phase itself (DNA replication stimulation)
    • G2 to M transition (mitosis commencement)

G1 to S Transition

  • Cyclins: Cyclin D and Cyclin E
  • Cdks: Cdk4 and Cdk2, respectively (Cyclin D with Cdk4, Cyclin E with Cdk2).
  • Assist in moving from G1 into S phase.

S Phase

  • Cyclin: Cyclin A
  • Cdk: Cdk2
  • Cyclin A and Cdk2 pair up to phosphorylate other proteins, stimulating DNA replication

G2 to M Transition

  • Cyclin: Cyclin B
  • Cdk: Cdk1
  • Mitosis Promoting Factor (MPF) is stimulated.
  • Cyclin B and Cdk1 phosphorylate MPF.
  • This moves the cell from G2 into M phase and cell division.

G1 to S Transition (Detailed)

  • Most important transition; commitment to cell division.
  • Cyclin D and Cdk4, and Cyclin E and Cdk2 phosphorylate Retinoblastoma protein (RB).
  • RB is an inhibitor of the cell cycle (acts as a brake).
  • Genes responsible for proteins that act as brakes are tumor suppressors.
  • Phosphorylation of RB inactivates it, removing the brake and allowing passage through the restriction point into S phase.

Other Tumor Suppressors

  • p21
  • p53

p53

  • Always present; "guardian of the genome."
  • Activated by UV radiation, which stimulates protein kinases leading to p53 phosphorylation
  • Phosphorylated p53 enters the nucleus and stimulates p21 production.

p21

  • Produced only when necessary.
  • Inhibits cyclin and Cdk pairs, stopping the cell cycle.
  • Prevents cyclin-Cdk from phosphorylating RB.
  • Allows the cell to repair itself or undergo apoptosis.

Cell Death

Necrosis

  • Occurs when cells are damaged or starved of oxygen or nutrients.
  • Cells burst or rupture, causing inflammation that affects neighboring cells.
  • Takes several days.

Apoptosis

  • Programmed cell death; a physiologic response.
  • Cells self-destruct.
  • Membranes bleb, and DNA is cut into small pieces by caspases.
  • No inflammation; no damage to neighboring cells.
  • Takes only a few hours.
  • Occurs when cells are too old or no longer needed (e.g., embryologic development).

Apoptosis Signals

Internal

  • Issue within the cell (e.g., DNA damage).
  • p53 is stimulated.
  • p53 stimulates BAX, which causes cytochrome c to be released from the mitochondria.
  • Cytochrome c stimulates the production of caspases, which cut the DNA into segments.

External

  • Immune system detects infected or cancerous cell.
  • Fas on the cell surface binds to Fas ligands.
  • This stimulates production of caspases, which cut up the DNA.