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.