Overview
This lecture explains how the cell cycle is regulated by internal and external mechanisms, details the three main cell-cycle checkpoints, and describes the molecules responsible for positive and negative regulation of cell division.
Variability and Timing in the Cell Cycle
- The length of the cell cycle varies between cell types and organisms.
- Human cell cycles can range from hours (early embryos) to a lifetime (non-dividing specialized cells).
- Typical rapidly dividing human cells have a ~24-hour cell cycle: G1 (9h), S (10h), G2 (4.5h), M (0.5h).
- Cell cycle timing is controlled by both internal and external mechanisms.
External Regulation of the Cell Cycle
- Events outside of the cell (e.g., hormones, cell death, crowding) can initiate or inhibit cell division.
- Human growth hormone (HGH) promotes cell division; lack can cause dwarfism, excess can cause gigantism.
- Increased cell size may trigger division due to decreased surface-to-volume ratio.
Internal Checkpoints in the Cell Cycle
- Three primary checkpoints halt cycle progression until conditions are favorable: G1, G2, and M (metaphase).
- G1 checkpoint: checks for adequate resources, size, and DNA damage.
- G2 checkpoint: ensures DNA replication is complete and undamaged.
- M checkpoint: confirms all chromatids are properly attached to spindle fibers before separation.
Positive Regulation of the Cell Cycle
- Cyclins and cyclin-dependent kinases (Cdks) are positive regulators that drive progression through checkpoints.
- Cyclin levels fluctuate predictably throughout the cycle, determining Cdk/cyclin complex formation.
- Cdks are kinases that phosphorylate target proteins to advance the cell cycle.
- Cdk/cyclin complex activation requires cyclin binding and phosphorylation.
Negative Regulation of the Cell Cycle
- Negative regulators prevent the cycle from progressing under problematic conditions.
- Cdk inhibitors block activation of Cdk/cyclin complexes until events are properly completed.
- Key negative regulators: retinoblastoma protein (Rb), p53, and p21.
- p53 halts the cycle or triggers apoptosis in response to DNA damage; induces p21 to inhibit Cdk/cyclin activity.
- Rb binds transcription factors (e.g., E2F) to block G1/S transition until the cell grows and Rb is inactivated.
Key Terms & Definitions
- Cell cycle — the ordered series of events involving cell growth and division.
- Checkpoints — control points where the cell assesses readiness to proceed to the next phase.
- Cyclins — proteins whose concentrations regulate cell cycle progression.
- Cyclin-dependent kinases (Cdks) — enzymes that, when bound to cyclins, phosphorylate proteins to advance the cell cycle.
- Cdk inhibitors — molecules that block Cdk/cyclin complex activation.
- Retinoblastoma protein (Rb) — a tumor suppressor that halts the cycle until the cell is ready to divide.
- p53 — a protein that responds to DNA damage by halting the cycle or inducing apoptosis.
- p21 — a protein induced by p53 that inhibits Cdk/cyclin complexes.
Action Items / Next Steps
- Watch an animation of the cell cycle checkpoints at the linked website.
- Review examples of cell-cycle regulation and checkpoint control.
- Ensure understanding of key regulatory proteins and checkpoint mechanisms for assessment.