Cell Biology: Regulation of Cell Cycle

Cell Biology: Regulation of Cell Cycle

• Multicellular organisms need coordinated cell division across tissues and organs for normal growth, development, and maintenance
• The timing and rates of cell division are coordinated, but not all cells have the same cell cycle
• Cell division frequency varies by cell type, with examples of fast division in embryos (<20 minutes) and slower division in liver cells (12-24 hours). Mature nerve and muscle cells do not divide after maturity but are permanently in G0

Frequency of Cell Division

• Embryo cell cycle <20 minutes
• Skin cells divide frequently throughout life (12-24 hours)
• Liver cells retain the ability to divide but divide rarely
• Mature nerve and muscle cells do not divide after maturity and permanently stay in G0

Overview of Cell Cycle Control

• Two irreversible points in the cell cycle are the replication of genetic material and the separation of sister chromatids
• Checkpoints assess the cell cycle's progress and may halt processes if needed

Checkpoint Control System

• Cell cycle is controlled by STOP and GO chemical signals at critical points
• Signals indicate if key cellular processes have been completed correctly
• Three major checkpoints:
  • G1/S checkpoint: Checks if DNA synthesis can begin
  • G2/M checkpoint: Checks if DNA synthesis is completed correctly and commits to mitosis
  • Spindle checkpoint: Ensures all chromosomes are attached to the spindle and sister chromatids can separate correctly

G1/S Checkpoint

• Critical primary decision point ("restriction point")
• Internal signals (cell growth, nutrition)
• External signals (growth factors)
• If cell does not receive "go" signal, it exits the cycle and enters G0 phase (non-dividing, working state)

G0 Phase

• Non-dividing, differentiated state
• Most human cells are in G0
• In G0, cells can be "called back" to the cell cycle by external cues

Activation of Cell Division

• Cells use cell communication signals
• Chemical signals in the cytoplasm give cues. The signals are often proteins (activators or inhibitors)
• "Go-ahead" signals: Promote cell growth and division (internal signals - "promoting factors", external signals - "growth factors")
• Primary mechanism of control: Phosphorylation

Cell Cycle Signals

• Cell cycle controls regulate cyclin (regulatory protein) levels; their levels cycle in cells
• Cyclin-dependent kinases (Cdks) phosphorylate cellular proteins – activating or inactivating them
• Cdk-cyclin complex triggers passage through different stages of cell cycle

Cyclins & Cdks

• Interactions of Cdks and different cyclins trigger the stages of the cell cycle
• Genes for regulatory proteins are highly conserved throughout evolution

G2/M and Spindle Checkpoints

• G2/M checkpoint: verifies replication completion and DNA integrity
• Spindle checkpoint: ensures chromosomes are attached to metaphase plate for proper cytokinesis

External Signals

• Growth factors:
  • Coordination between cells
  • Released proteins stimulating other cells to divide
  • Density-dependent inhibition: Crowded cells stop dividing
  • Anchorage dependence: Cells must be attached to a substrate to divide
• Growth factor signals: -Growth factor binds to cell-surface receptor. This initiates a cascade of protein kinase activation and leads to phosphorylation events.

Example of a Growth Factor

• Platelet-derived growth factor (PDGF) is made by platelets in blood clots. It stimulates cell division in fibroblasts.

Growth Factors and Cancer

• Normal genes (proto-oncogenes) can become oncogenes (cancer-causing) when mutated. They stimulate cell growth and are often switched "ON". This contrasts with tumor-suppressor genes that inhibit cell division. An example is switched "OFF," which can cause cancer (like p53)
• This is a critical regulatory system.

Cancer & Cell Growth

• Cancer results from a failure of cell division control (uncontrolled growth)
• Loss of checkpoint stops
• p53 protein critically regulates DNA repair or cell death if DNA is severely damaged. This is a key G1/S restriction point.

Development of Cancer

• Cancer development requires multiple mutations ("hits")
• These hits can be caused by various factors such as UV radiation, chemical exposure, radiation, heat, cigarette smoke, and genetics.

Tumors

• Benign tumors are masses of abnormal cells that remain at the original site, often as a lump. p53 often halts cell division in benign tumors
• Malignant tumors are masses of abnormal cells that spread (metastasize). These cells can detach from the original site, enter blood or lymph, and start tumors in other tissues.

Traditional Cancer Treatments

• Treatments target rapidly dividing cells, such as high-energy radiation, chemotherapy, and drugs that interfere with DNA replication, mitosis, cytokinesis, and blood vessel growth.