Lecture 48: Tumor Suppressor Genes Flashcards
What do Tumor Suppressor genes do?
-Which normally inhibit growth
-Cell cycle control genes, apoptosis
promoting genes and/or DNA repair genes
Loss of function: Cause cancer when they stop working
Wilms Tumor
- AD inheritance
- Loss of function of WT1 gene (tumor suppressor)
- Chrom 11
Sporadic cancer
- Inherited two normal tumor suppressor alleles, but then later one cell loses one of its gene = first hit
- Then second allele is lost = second hit = Loss of Heterozygosity (LOH)
Identifiers:
- Presents with one tumor
- Unilateral (in one cell in the body)
- Skips generations in a pedigree
- Later onset
Familial cancer
-Inherited one normal tumor suppressor allele, then later in life second allele is lost = cancer
Identifiers:
- Presents with multiple tumors
- Bilateral (all cells have first hit)
- Doesn’t skip generations in a pedigree (Family history)
- Earlier onset
Mechanisms producing 2nd hit
1) Point mutation
2) Gene deletion (Most common)
3) Mitotic recombination
4) Loss through non-disjunction
5) Methylation of gene (still present but silenced)
Rb protein
At G1/S checkpoint -CDK 4/6 --> constantly made -Cyclin D -Rb no longer represses E2F -E2F activates S-phase genes (Cell divides)
No cyclin/Cdk
- Transcription blocked
- Arrested in G1
- Deacetylation
Hyperphosphorylated Rb
Hypophosphorylated Rb
Cyclins/Cdk HYPERphosphorylate
- Rb doesn’t repress E2F + activates S-Phase genes
- Cell cycle progresses, cell division, no G1 arrest
No cyclin/Cdk present = HYPOphosphorylated Rb
- Rb/E2F complex still binds to DNA + gets methylase and histone deacetylase
- Cell cycle arrested, no cell division, arrested in G1
How does the loss of Rb effect the cell cycle?
Loss of Rb/ mutant Rb, does NOT bind to E2F → Increased
transcription of S phase genes (Unregulated cell division)
What is a criteria all cancers show?
Dysregulation of the G1-S checkpoint
Mutation in one of these 4 genes:
1) RB –> Inhibitor of E2F
2) CDK4
3) Cyclin D gene
4) CDKN2A (p16).
(G1 CDK complex inactivates Rb by phosphorylation)
Retinoblastoma
-Mutation of Rb gene on chromosome 13
Symptom:
-White pupillary reflex
p53
- Tumor suppressor protein = “guardian of genome”
- G1/S checkpoint
- Cell Cycle Control (Cell Birth)
- Apoptosis Control (Cell Death) –> (Bax promotes apop.)
- Increases DNA repair capabilities
-Loss of p53 function results in net cell growth, and increased mutation = cancer progression
How does p53 influence apoptosis
-Activates intrinsic and extrinsic pathways for apoptosis
p53 increases:
- Bax (promotes apoptosis)
- Fas receptor (CD95)
- IGFBP-3 (sequesters cell survival proteins like IGF1/2 away from receptors)
Li-Fraumeni syndrome
- Inherited mutation in p53
- 1st hit = inherited from mom
- 2nd hit = somatic (LOH)
- Breast, bone, brain, and soft-tissue carcinomas
Common Inherited Cancers
1) Colorectal cancer
- FAP
- HNPCC
- Most non-familial
2) Breast/Ovarian
Familial Adenomatous Polyposis (FAP)
- AD disorder
- High penetrance
- Tumor suppressor gene (affects B-catenin involved in growth control pathway)
- Many different mutations of the APC gene = (Allelic heterogeneity)
Normal APC pathway: WNT Signal present
-APC encodes a tumor suppressor
1) Destruction complex inactivated
2) B-Catenin not degraded
3) B-Catenin moves to nucleus = complex w TCF-4
= Growth promoting genes
APC Pathway: No WNT signal
1) APC interacts w/ B-catenin
2) Phosphorylation of B-catenin
3) Ubiquitination and B-catenin degraded
= low B-catenin degradation
*With mutated APC, it doesn’t interact w B-catenin, B-catenin interacts w TCF-4 = activation of growth
Hereditary Non-Polyposis Colon Cancer
(HNPCC): Lynch Syndrome
- Mutation of DNA mismatch repair (MMR) genes
- Cells accumulate mutations
- Tumors have microsatellite instability = Tandem repeats
- Fewer polyps
- Accelerated tumor progression
Genes responsible:
1) MSH2
2) MLH1
3) PMS1/2
FAPS
- APC mutation
- Accelerated Initiation
- Numerous Polyps
- Normal tumor progression
Breast Cancer
Ovarian Cancer
Breast Cancer
- BRCA1 (Allelic heterogeneity) and BRCA2 code for breast cancer type 1 and 2 susceptibility protein
- If lost cells can duplicate with DNA damage = cancer
Ovarian Cancer
-BRCA2
Epigenetics in Tumorigenesis
-Tumor suppressors are frequently HYPERmethylated in cancer cells (silencing tumor suppressor genes) = cancer progression
- Loss of imprinting = growth
- MicroRNAs
MicroRNA in Tumorigenesis
-MicroRNA reduces expression of genes
Reduction of miRNA could be inhibited oncogene RNA
-Increase in miRNA that inhibit tumor suppressor RNA
Expression array analysis and cancer
-Helps classify cancer and therapy needed
Microarray Analysis:
-Can determine changes in the expression of large numbers of genes between two groups
