Regulation of the Cell Cycle and Cancer

Chapter 12: The Cell Cycle, Regulation, and Cancer

Overview of the Cell Cycle

The cell cycle is a series of events that cells go through as they grow and divide. It consists of distinct phases that ensure proper cell growth, DNA replication, and division.

• Phases of the Cell Cycle:

  • G1 (First Gap): Cell grows and carries out normal functions.

  • S (Synthesis): DNA is replicated.

  • G2 (Second Gap): Cell prepares for division.

  • M (Mitosis and Cytokinesis): Cell divides its nucleus and cytoplasm.

• Interphase: Includes G1, S, and G2 phases; the cell is not dividing but is metabolically active.

• Division: Includes mitosis (nuclear division) and cytokinesis (cytoplasmic division).

Control of the Cell Cycle

Cell cycle length and progression are tightly regulated and can vary among cell types and conditions.

• Rapidly Dividing Cells: Have a short G1 phase (e.g., embryonic cells).

• Non-dividing Cells: Some cells enter a permanent arrested state called G0 (e.g., neurons, muscle cells).

• Regulation: The cell cycle is controlled by precise molecular mechanisms that respond to internal and external signals.

Discovery of Cell Cycle Regulatory Molecules

Key discoveries in the 1970s and 2001 (Nobel Prize) identified molecules that regulate the cell cycle, including the M phase-promoting factor (MPF).

• M phase-promoting factor (MPF): Induces mitosis in all eukaryotic cells.

• Regulatory Proteins: Cyclins and cyclin-dependent kinases (Cdks) are central to cell cycle control.

What is MPF?

MPF is a dimer composed of two distinct proteins that regulate entry into mitosis.

• Cyclin: A regulatory protein whose concentration fluctuates throughout the cell cycle.

• Protein kinase (Cdk): An enzyme that catalyzes the transfer of a phosphate group from ATP to a substrate, activating or deactivating target proteins.

Regulation of MPF Activity

MPF activity is controlled by cyclin concentration and phosphorylation events.

• Activation: Cdk has two phosphorylation sites; both are phosphorylated after cyclin binds, but MPF is not active until one phosphate is removed in late G2 phase.

• Function: Active MPF phosphorylates proteins to initiate mitosis, such as those involved in chromosome condensation and spindle formation.

• Deactivation: During anaphase, cyclin is tagged for destruction, leading to MPF inactivation. This is an example of negative feedback.

Cell Cycle Checkpoints

Checkpoints are critical control points where regulatory molecules determine whether the cell should proceed to the next stage.

• G1 Checkpoint: Determines if the cell will continue to divide or enter G0.

• G2 Checkpoint: MPF activation allows entry into mitosis.

• M Checkpoint: Ensures proper chromosome attachment before division.

• Checkpoint Regulators: Ensure cells only divide when appropriate.

Role of p53 in the Cell Cycle

p53 is a tumor suppressor protein that acts as a brake on the cell cycle in response to DNA damage.

• Activation: Stabilized when DNA damage is detected.

• Function: Activates proteins to pause the cell cycle and repair damage; can initiate apoptosis if damage is excessive.

• Importance: Prevents propagation of mutations; defective p53 is found in many cancers.

Cell Cycle and Cancer

Cancer results from uncontrolled cell division due to failed cell cycle checkpoints.

• Characteristics:

  • Uncontrolled division

  • Invasion of nearby tissues

  • Metastasis (spread to other sites)

• Types of Tumors:

  • Benign: Noncancerous, noninvasive

  • Malignant: Cancerous, invasive, can metastasize

• Genetic Defects:

  • Mutations that activate proteins required for division ("gas pedal")

  • Mutations that inactivate tumor suppressor genes ("brakes")

  • Most mutations are somatic; only ~10% are inherited

Common Cancer Mutations and the G1 Checkpoint

Many cancer-causing mutations affect the G1 checkpoint, leading to uncontrolled cell division.

• Overproduction of G1 Cyclin: Permanently activates Cdk, continuously phosphorylates Rb, preventing it from binding E2F.

• Defective Rb: Cannot bind E2F, allowing S phase genes to be activated inappropriately.

• Defective p53: DNA damage is not repaired, leading to rapid mutation accumulation.

Summary Table: Cell Cycle Phases and Key Regulators

Phase	Main Event	Key Regulator(s)
G1	Cell growth, normal function	G1 Cyclin, Cdk, p53
S	DNA synthesis	E2F, Rb
G2	Preparation for mitosis	MPF (Cyclin + Cdk)
M	Mitosis, cytokinesis	MPF, checkpoint proteins

Key Equations and Concepts

• Protein Kinase Reaction:

$\text{Protein} + \text{ATP} \xrightarrow{\text{Kinase}} \text{Protein-P} + \text{ADP}$

• Negative Feedback Example: Cyclin degradation turns off MPF activity.

Example: Cell Cycle Regulation in Cancer

In many cancers, mutations in genes encoding cyclins, Cdks, Rb, or p53 disrupt normal cell cycle control, leading to unchecked cell division and tumor formation.

Additional info: The notes above expand on the original slides by providing definitions, context, and examples for key terms and processes, ensuring a self-contained study guide for exam preparation.