Cell Cycle and p53 Protein Functions

Cell Biology: Regulation of Cell Cycle

• Multicellular organisms need coordinated cell division across tissues and organs. This is crucial for normal growth, development, and maintenance.
• Timing and rates of cell division must be coordinated across different cells.
• Not all cells have the same cell cycle.

Frequency of Cell Division

• Cell cycle frequency varies by cell type.
• Embryo cells have a cycle less than 20 minutes.
• Skin cells divide frequently (12-24 hours).
• Liver cells divide every year or two.
• Mature nerve and muscle cells do not divide after maturity; they are permanently in G0 phase.

Overview of Cell Cycle Control

• Two irreversible points in the cell cycle are replication of genetic material and separation of sister chromatids.
• Checkpoints in the cell cycle assess the process and halt it if necessary.

Checkpoint Control System

• Cell cycle progression is controlled by "STOP & GO" chemical signals at critical points.
• Signals indicate if cellular processes have been completed correctly.

3 Major Checkpoints

• G₁/S: Determines if DNA synthesis can begin.
• G₂/M: Checks if DNA synthesis has been completed correctly and if the cell is ready for mitosis.
• Spindle: Ensures all chromosomes are attached to the spindle and sister chromatids can separate correctly.

G1/S Checkpoint

• This checkpoint is the most critical primary decision point ("restriction point").
• If the cell receives signals (internal, like growth size and nutrition; external, like growth factors), it divides.
• If the cell does not receive these signals, it exits the cycle and enters the G0 phase (non-dividing state).

Go Phase

• The Go phase is a non-dividing, differentiated state.
• Many human cells are in the Go phase.
• Examples include liver cells, which can re-enter the cycle under certain conditions. Also nerve and muscle cells.
• Highly specialized cells remain in Go and will never divide.

Activation of Cell Division

• Cells communicate to determine when to divide through chemical signals in the cytoplasm, often proteins (activators and inhibitors).

"Go-ahead" Signals

• Protein signals that promote cell growth and division.
• Internal signals (promoting factors).
• External signals (growth factors).
• Primary mechanism is phosphorylation by kinase enzymes.

Cell Cycle Signals

• Cyclins, proteins with fluctuating levels in the cycle.
• Cyclin-dependent kinases (Cdks), kinases that are activated by binding to cyclins; phosphorylate proteins during specific stages of the cycle.
• Cdk-cyclin complexes trigger transition through cell cycle stages.

Cyclins & Cdks

• Interaction of cyclins and Cdks is crucial to trigger cell cycle progression through the specific phases.

G₂/M Checkpoint

• Checks replication completion and DNA integrity.
• Important for preventing cells with damaged DNA from progressing.

Spindle Checkpoint

• Ensures chromosomes attach properly to spindles for accurate sister chromatid separation.

External Signals

• Growth factors: signals released by body cells that stimulate cell division (coordination between cells).
• Density-dependent inhibition: cells stop dividing when crowded due to insufficient growth factors.
• Anchorage dependence: cells must be attached to a substrate to divide.

Growth Factor Example: PDGF

• Platelet-derived growth factor (PDGF) stimulates cell division (fibroblasts) in wound healing.

Growth Factors and Cancer

• Proto-oncogenes: Normal genes that can become oncogenes, leading to uncontrolled cell growth when mutated. Example: RAS.
• Tumor-suppressor genes: Inhibit cell division; if switched off can lead to cancer. Example p53.

Cancer & Cell Growth

• Cancer results from uncontrolled cell growth due to a failure in the cell cycle's control mechanisms.
• Key mutations ("hits") are involved in different stages of cancer development.
• p53 protein is a crucial tumor suppressor that controls DNA damage response. It halts cell division if DNA damage is detected.

p53 - Master Regulator Gene

• p53 plays a key role in cell cycle control.
• If p53 is dysfunctional, damaged DNA can cause uncontrolled division.

Development of Cancer

• Cancer develops after multiple mutations (hits) in key genes.
• Mutations can be prompted by agents such as radiation, chemicals, pollution, smoking, genetics and more.

Tumors

• Benign tumors: abnormal cells remain at the original site; usually not life-threatening.
• Malignant tumors: cells leave original site, spread (metastasis), and negatively impact organ function.

Traditional Treatments for Cancers

• Treatments target rapidly dividing cells in cancers.
  • Examples include high-energy radiation, chemotherapy, and drugs that stop DNA replication, mitosis, and cytokinesis and blood vessel growth.