21.2 Tumor suppressors and proto-oncogenes

Tumor Suppressors and Proto-Oncogenes

Cancer develops when mutations hit two categories of genes that normally keep cell growth in check. Tumor suppressor genes act as brakes on the cell cycle, while proto-oncogenes are normal genes that, when mutated, become oncogenes that accelerate growth. The interplay between lost brakes and a stuck accelerator is central to understanding how normal cells become cancerous.

Functions of Tumor Suppressor Genes

Tumor suppressors exist to prevent cells from dividing when they shouldn't. They do this through several mechanisms:

• Inhibit cell cycle progression, particularly at the G1-to-S phase checkpoint, ensuring cells don't replicate damaged DNA
• Promote apoptosis (programmed cell death) to eliminate cells that are too damaged to repair
• Maintain genomic stability by detecting DNA damage and activating repair pathways. p53 is the classic example of this role.
• Act as gatekeepers against uncontrolled proliferation and tumor formation

Major tumor suppressor genes you should know: p53, RB1, BRCA1, BRCA2, APC, and PTEN.

Mutations in Cancer Development

Cancer doesn't usually result from a single mutation. It typically requires the accumulation of mutations across multiple genes, affecting both tumor suppressors and proto-oncogenes.

Loss-of-function mutations in tumor suppressors:

• The protein product is reduced or absent, so the "brake" no longer works
• Cells lose proper cell cycle regulation and divide unchecked
• Damaged cells that should undergo apoptosis instead survive and accumulate further mutations

This follows the two-hit hypothesis (Knudson's model): because you carry two copies of each tumor suppressor gene, both copies must be inactivated before the brake is fully lost. In hereditary cancers, a person inherits one defective copy and only needs one somatic mutation to lose function. In sporadic cancers, both hits must occur in the same cell during a person's lifetime.

Gain-of-function mutations in proto-oncogenes:

• A single activating mutation in just one copy is enough to create an oncogene (these act dominantly)
• The resulting protein is either constitutively active (always "on") or overexpressed
• Cells receive growth and survival signals even without normal external growth factors

Together, the loss of tumor suppressors and the activation of oncogenes give cancer cells their hallmark traits: sustained proliferation, resistance to cell death, and genomic instability.

Examples of Cancer-Related Genes

p53 is mutated in over 50% of all human cancers, including lung, breast, and colorectal cancers. It's called the "guardian of the genome" because it sits at the center of the DNA damage response. When p53 is lost, cells with broken DNA keep dividing instead of arresting or dying.

BRCA1 and BRCA2 are involved in repairing double-strand DNA breaks through homologous recombination. Inherited mutations in either gene dramatically increase the risk of breast and ovarian cancer because cells can no longer accurately fix their most dangerous type of DNA damage.

APC is a tumor suppressor that regulates the Wnt signaling pathway, which controls cell proliferation and adhesion. Mutations in APC cause familial adenomatous polyposis (FAP), where hundreds of polyps form in the colon, and are also found in most sporadic colorectal cancers. Loss of APC leads to constitutive Wnt signaling and unchecked growth.

RAS is a proto-oncogene mutated in roughly 30% of all cancers, with especially high rates in pancreatic (~95%), lung, and colorectal cancers. Normal RAS acts as a molecular switch that relays growth factor signals. Oncogenic RAS is stuck in the "on" position, continuously driving proliferation.

MYC is a transcription factor that activates genes for cell growth, proliferation, and metabolism. It's amplified or overexpressed in many cancers, including Burkitt's lymphoma (where a chromosomal translocation places MYC under control of a highly active immunoglobulin promoter) and neuroblastoma.

Mechanisms of Cell Growth Regulation

These genes don't work in isolation. Here's how the major players regulate growth at the molecular level:

1. p53 pathway

• DNA damage or cellular stress stabilizes and activates p53
• p53 induces transcription of p21, which inhibits cyclin-dependent kinases (CDKs), halting the cell cycle at G1
• If damage is irreparable, p53 triggers apoptosis by upregulating pro-apoptotic proteins (Bax, PUMA) and downregulating anti-apoptotic proteins (Bcl-2)

2. RB1 pathway

• In its active (hypophosphorylated) state, RB1 binds and sequesters E2F transcription factors, blocking transcription of genes needed for S phase entry
• When the cell receives appropriate growth signals, CDK-cyclin complexes phosphorylate RB1, releasing E2F and allowing the cell cycle to proceed
• Loss of RB1 means E2F is always free, so cells enter S phase without proper checkpoints

3. PTEN and the PI3K/AKT pathway

• PTEN is a phosphatase that dephosphorylates $PIP_3$, directly opposing the PI3K/AKT survival and growth pathway
• When PTEN is lost, $PIP_3$ accumulates, AKT is constitutively active, and cells receive constant pro-survival and pro-growth signals

4. RAS signaling

• Growth factors bind receptor tyrosine kinases (RTKs), which activate RAS
• Active RAS triggers two key downstream cascades: RAF → MEK → ERK (drives proliferation) and PI3K → AKT (promotes survival)
• Oncogenic RAS mutations lock the protein in its GTP-bound active state, so these pathways fire continuously regardless of external signals

5. MYC as a transcriptional amplifier

• MYC binds promoter regions of target genes and recruits transcriptional machinery to boost expression of genes involved in growth and metabolism
• Overexpression of MYC pushes cells into rapid, uncontrolled proliferation because it amplifies the transcriptional output of growth programs