Cell Cycle Regulation and Cancer
The Cell Cycle
The cell cycle is the ordered sequence of events that occurs from one cell division to the next. It consists of interphase (G1, S, and G2 phases) and the mitotic phase (mitosis and cytokinesis).
Phases of the Cell Cycle
| Phase | Events | Duration (typical) |
|---|---|---|
| G1 (Gap 1) | Cell growth; organelle production; protein synthesis; cell prepares to replicate DNA | Variable (hours to years) |
| S (Synthesis) | DNA replication — each chromosome is copied to form two sister chromatids joined at the centromere | ~8 hours |
| G2 (Gap 2) | Further growth; synthesis of proteins needed for mitosis (e.g. tubulin for spindle); organelle replication; error checking of replicated DNA | ~4-6 hours |
| M (Mitotic) | Nuclear division (mitosis) followed by cytoplasmic division (cytokinesis) | ~1 hour |
Some cells exit the cycle and enter G0, a quiescent state where the cell is metabolically active but not preparing to divide. Mature neurones and muscle cells are typically in G0 permanently.
Cell Cycle Checkpoints
The cell cycle is regulated by a series of checkpoints — control points where the cell assesses whether conditions are suitable to proceed. If problems are detected, the cycle is halted until they are resolved (or the cell is directed to undergo apoptosis).
The Three Major Checkpoints
G1 checkpoint (Restriction Point):
- Checks whether the cell is large enough to divide
- Checks for DNA damage — if detected, the cycle is paused to allow repair
- Checks for growth factor signals from the external environment
- If conditions are not met, the cell enters G0
- This is the primary decision point — once a cell passes it, it is committed to division
G2 checkpoint:
- Checks that DNA replication is complete and accurate
- Checks for any DNA damage that occurred during S phase
- Ensures the cell has sufficient proteins and organelles for mitosis
M checkpoint (Spindle Assembly Checkpoint):
- Occurs during metaphase of mitosis
- Checks that all chromosomes are correctly attached to spindle fibres at their kinetochores
- Prevents progression to anaphase until every chromosome is properly aligned
- Failure of this checkpoint can lead to aneuploidy
Molecular Regulators
Cyclins and Cyclin-Dependent Kinases (CDKs)
The cell cycle is driven by cyclins — proteins whose concentration rises and falls cyclically — and cyclin-dependent kinases (CDKs) — enzymes that are only active when bound to a cyclin partner.
- Cyclins are synthesised and degraded at specific points in the cycle
- When a cyclin binds to its CDK partner, the resulting cyclin-CDK complex phosphorylates target proteins that drive the cell into the next phase
- For example, cyclin D accumulates in G1 and activates CDK4/6, promoting passage through the G1 checkpoint
- Cyclin B paired with CDK1 (also called MPF — maturation promoting factor) triggers entry into mitosis
The sequential activation and destruction of different cyclin-CDK complexes acts as a molecular clock that ensures the cell cycle progresses in the correct order.
Tumour Suppressor Genes
Tumour suppressor genes code for proteins that inhibit cell division or promote apoptosis. They act as brakes on the cell cycle.
p53 — The Guardian of the Genome:
- The TP53 gene encodes the p53 protein
- When DNA damage is detected, p53 halts the cell cycle at G1 by activating transcription of p21, a CDK inhibitor
- p21 binds to and inhibits cyclin-CDK complexes, preventing the cell from entering S phase
- If the damage is irreparable, p53 triggers apoptosis (programmed cell death)
- p53 is mutated in over 50% of all human cancers
Rb (Retinoblastoma protein):
- Normally inhibits transcription factors (E2F) needed for S-phase entry
- When phosphorylated by cyclin-CDK complexes in response to growth signals, Rb releases E2F, allowing S-phase genes to be expressed
- Loss of functional Rb removes this brake, allowing uncontrolled entry into S phase
Proto-oncogenes and Oncogenes
Proto-oncogenes code for proteins that stimulate cell division — growth factors, growth factor receptors, signal transduction proteins, and transcription factors. They are normal, essential genes.
An oncogene is a mutated proto-oncogene that is permanently active or overexpressed, driving continuous cell proliferation without the normal regulatory signals. Examples:
- RAS — normally a signal transduction protein activated by growth factor binding. Mutant Ras is locked in the active form, continuously signalling the cell to divide. Mutated in ~30% of cancers.
- HER2 — codes for a growth factor receptor. Amplification of HER2 is found in some breast cancers, leading to overexpression of the receptor and excessive growth signalling.
- MYC — a transcription factor. Overexpression drives uncontrolled progression through the cell cycle.
Cancer: Loss of Cell Cycle Control
Cancer results from the accumulation of mutations that disrupt the normal regulation of the cell cycle. A cancerous cell divides uncontrollably, forming a tumour.
The Multi-Hit Hypothesis
Cancer typically requires multiple mutations in the same cell lineage — usually in both tumour suppressor genes and proto-oncogenes. This is known as the multi-hit (or multi-step) hypothesis. This explains why cancer risk increases with age, as mutations accumulate over a lifetime.
Characteristics of Cancer Cells
- Uncontrolled proliferation — divide without growth factor signals
- Ignore checkpoint signals — bypass G1 and other checkpoints
- Evade apoptosis — resist programmed cell death (often due to p53 loss)
- Immortality — activate telomerase to maintain telomere length, avoiding the Hayflick limit
- Angiogenesis — stimulate growth of new blood vessels to supply the tumour
- Metastasis — break away from the primary tumour, enter the blood or lymph, and establish secondary tumours at distant sites
Benign vs Malignant Tumours
| Feature | Benign | Malignant |
|---|---|---|
| Growth rate | Slow | Often rapid |
| Encapsulated? | Yes | No |
| Invasion of surrounding tissue | No | Yes |
| Metastasis | No | Yes |
| Life-threatening? | Rarely (unless pressing on vital structures) | Often |
Causes of Cancer (Mutagens and Carcinogens)
- Chemical carcinogens — e.g. tar in cigarette smoke (contains benzpyrene), asbestos
- Ionising radiation — UV light (causes thymine dimers), X-rays, gamma rays
- Viruses (oncogenic viruses) — e.g. HPV (human papillomavirus) produces proteins that inactivate p53 and Rb
- Inherited mutations — e.g. BRCA1/BRCA2 mutations increase breast cancer risk
Exam Tips
- AQA expects you to explain cancer in terms of mutations in both tumour suppressor genes AND proto-oncogenes — a complete answer mentions both categories
- Always distinguish between a proto-oncogene (normal) and an oncogene (mutated/overactive)
- p53 questions are very common — remember the pathway: DNA damage → p53 activation → p21 transcription → CDK inhibition → cell cycle arrest (or apoptosis)
- When asked about the relationship between cancer and age, link to the accumulation of mutations over time (multi-hit hypothesis)