rb and tumor supressors

chap 4 exam 1

What is the main function of tumor suppressor genes?

They act like the cell’s brakes, stopping uncontrolled division. They regulate the cell cycle, repair DNA damage, and prevent cells with errors from dividing.

What happens if tumor suppressor genes are mutated or deleted?

The brakes are lost, so cells can divide uncontrollably, leading to cancer.

What is the Two-Hit Hypothesis?

Both copies (alleles) of a tumor suppressor gene must be mutated for cancer to form.

Why are two hits needed for Rb, but only one for an oncogene like Src?

Oncogenes are like gas pedals (one stuck pedal is enough). Tumor suppressors are like brakes (one working brake still slows the car; need both gone to lose control).

What are the key jobs of tumor suppressor genes?

1. Control cell cycle checkpoints

2. Stop mitosis unless needed

3. Help repair DNA damage

4. Trigger apoptosis if damage is too severe

What hallmark of cancer is linked to tumor suppressor loss?

Evading growth suppressors

What is Loss of Heterozygosity (LOH)?

When one parent’s copy of a gene is lost, leaving only the other.

Why is LOH important in cancer?

If the remaining allele is mutated, there’s no backup → tumor suppressor function lost → cancer develops.

What are the main causes of LOH?

• Deletion of a gene/chromosome part

• Gene conversion

• Mitotic recombination

• Loss of a whole chromosome

• Chromosomal rearrangements/instability

Why is LOH considered a “major mechanism” of cancer progression?

It removes the last working copy of a tumor suppressor gene, giving the cell a survival and growth advantage.

Who proposed the Two-Hit Hypothesis?

Alfred Knudson in the 1970s.

What cancer did Knudson study?

Retinoblastoma, a childhood eye cancer.

What did Knudson notice about inherited vs sporadic retinoblastoma?

• Inherited cases appeared earlier (2–6 months).

• Sporadic cases appeared later (2–4 years).

Why do inherited cases develop faster?

They are born with one mutated allele (“first hit”), so only one more mutation is needed.

Why do sporadic cases develop slower?

Both alleles must mutate during life, which takes more time.

Why do tumor suppressors usually need two hits to cause cancer?

They are recessive at the cellular level — one good copy can still function.

What is the role of Rb protein?

Rb is a gatekeeper for the cell cycle. It prevents the cell from moving from G1 to S phase until conditions are right.

How does Rb control cell division?

Rb binds and holds E2F, a transcription factor that activates DNA replication genes. This keeps E2F inactive until Rb is phosphorylated.

What is E2F?

E2F is a family of transcription factors that turn on genes needed for DNA synthesis and cell cycle progression into S phase.

What happens when Rb is phosphorylated?

It releases E2F, which then activates genes needed for S phase and cell proliferation.

What happens if Rb is missing or mutated?

E2F is always free → uncontrolled progression through the cell cycle → unchecked cell division.

Which cancers often involve Rb mutations?

Retinoblastoma, lung, bone, esophageal, breast, and bladder cancers.

Why is p53 called the “guardian of the genome”?

It protects the cell by stopping damaged DNA from being passed on, either by repair, pausing the cycle, or apoptosis.

What triggers p53 activation?

Stress signals like DNA damage, oncogene activation, or low oxygen. Kinases phosphorylate p53, stabilizing and activating it.

What type of protein is p53?

A transcription factor that binds DNA to turn on protective genes.

What form does functional p53 take?

A tetramer (four p53 proteins working together).

What does p53 do once activated?

• Turns on p21 to block the cell cycle

• Activates DNA repair genes

• Induces apoptosis genes (like BAX, PUMA, NOXA) if DNA is too damaged

Where do most p53 mutations occur?

In the DNA-binding domain.

What type of mutations are common in p53?

Mostly missense mutations, which create a faulty protein.

What happens to normal p53 levels in cells?

Normal p53 is kept low by MDM2 and MDM4.

• MDM2 tags p53 for destruction (ubiquitin-proteasome).

• MDM4 blocks p53’s transcription activity.

• Together they prevent p53 from building up until stress signals activate it.

What happens to mutant p53?

It accumulates in cells, doesn’t function, and can interfere with normal p53.

Why is targeting p53 in therapy difficult?

Mutant p53 builds up and interferes with normal processes.

Drugs aim to:

• Stop degradation of wild-type p53

• Restore function to mutant p53

What is the role of the APC gene?

APC is a negative regulator of the Wnt/β-catenin pathway.

What is β-catenin?

A signaling protein that, when free, moves into the nucleus and activates genes for cell division and migration.

How does APC normally regulate β-catenin?

APC forms a complex that binds β-catenin and leads to its degradation, stopping uncontrolled growth.

What happens when the Wnt pathway is active?

The surface complex blocks APC’s action → β-catenin is freed → enters nucleus → activates growth genes.

What happens if APC is mutated or lost?

β-catenin accumulates and keeps activating growth genes → uncontrolled cell proliferation.

In which cancer is APC mutation most common?

Colorectal cancer (in both inherited and sporadic forms).

What are common APC mutations?

• Germline: nonsense/deletions (truncated proteins)

• Somatic: missense mutations in β-catenin binding regions

What is the role of the VHL gene?

VHL targets HIF-1α for degradation under normal oxygen conditions.

What is HIF-1α?

Hypoxia-inducible factor 1 alpha, a transcription factor that activates genes for angiogenesis, survival, and metabolism when oxygen is low.

What happens if VHL is mutated or lost?

HIF-1α builds up even in normal oxygen → moves into nucleus → activates genes → promotes tumor growth and blood vessel formation.

What cancers are linked to VHL loss?

Renal cell carcinoma and angiomas.

What is the role of PTEN?

PTEN is a phosphatase that reverses PI3K signaling by converting PIP3 back into PIP2, turning off growth signals.

What is PI3K?

Phosphoinositide 3-kinase, an enzyme that converts PIP2 → PIP3, which promotes cell survival and proliferation.

What are PIP2 and PIP3?

Lipids in the cell membrane.

• PIP2 = inactive form

• PIP3 = active form that signals cell growth and survival

What happens if PTEN is mutated or lost?

PIP3 builds up → constant growth signaling → uncontrolled cell division and survival.

Does PTEN have roles besides growth signaling?

Yes, PTEN also helps with DNA repair.

Which cancers commonly lose PTEN?

Prostate cancer (~70% of cases) and glioblastoma (loss of chromosome 10 where PTEN is located).

Which tumor suppressor gene is most commonly mutated in cancer overall?

TP53

Which other tumor suppressors are commonly mutated?

PTEN, VHL, and APC

Which mutations are strongly linked to colon/rectal cancer?

APC and KRAS mutations

Which mutations are strongly linked to kidney cancer (KIRC)?

VHL and PBRM1 mutations

Which mutations are strongly linked to breast cancer?

PIK3CA mutations

Which mutations are strongly linked to brain cancer (GBM)?

EGFR mutations

What is haploinsufficiency?

When losing just one copy of a gene reduces function so much that cancer can develop.

Which tumor suppressors can show haploinsufficiency?

p27Kip1, p53, DMP1, NF1, and PTEN

What syndrome is linked to haploinsufficiency of p53?

Li-Fraumeni syndrome (LFS), caused by germline p53 mutations. Even with one normal allele, tumors still form

What’s an example of haploinsufficiency in Dmp1?

Losing one copy speeds up tumor growth because the single working copy cannot keep up with demand.