Lecture 65 Flashcards
What are four available paths that cause loss of heterozygosity (LOH) in retinoblastoma?
1) rb/+ –> rb/rb
2) Loss of chromosome with normal RB1 by mitotic non-disjunction (sometimes followed by duplication of remaining chromosome)
3) Mitotic crossing over proximal to RB1 locus
4) Deletion of normal RB1 allele
5) Point mutation in normal RB1 allele
How does the retinoblastoma protein regulate its cell cycle?
1) When RB1 is hypophosphorylated (In the G phases), it binds & inactivates transcription factor E2F
2) When RB1 is hyperphosphorylated, it releases E2F, allowing E2F to activate targets (S-phase)
3) If there is no RB1, there is no growth suppression
What is Li-Fraumeni syndrome?
1) Defective p53 protein
2) Wide variety of tumors that occur at an unusually young age (breast, brain, osteosarcoma, leukemia, etc.)
3) Inherited as an autosomal dominant predisposition to cancer
4) Mutations in TP53 (gene for checkpoint control protein p53) affect: DNA damage response & Apoptosis in response to genome instability
5) Individuals heterozygous for TP53 develop cancer at a frequency of >90-95% - point mutations in codon 245-258
6) Slightly more than 50% of all human cancers contain mutations in TP53 gene; the most frequently mutated of all known cancer genes
Normally, what is p53 bound to?
MDM2, which inactivates p53, so it is not used when it is not needed
What induces p53 to function?
1) DNA damage
2) Cell cycle abnormalities
3) Hypoxia
4) etc.
If there is low damage to a cell, what does p53 do?
1) Cell cycle arrest
2) DNA repair
3) Cell cycle restart
If there is high damage to a cell, what does p53 do?
1) Apoptosis
2) Destruction & elimination of damaged cells
Compare what occurs in cells with or without p53 when DNA damage occurs
1) DNA damage in WT cells: cells repaired before division, or killed
2) DNA damage in cells defective for p53: cells neither repaired before division, nor killed - mutation and proliferation of abnormal cells
What is neurofibromatosis?
1) Inherited as an autosomal dominant trait
2) Large numbers of benign neurofibromas
3) 3% of cases associated with malignant transformation
4) Mutation in Gatekeeper Tumor Suppressor Gene NF1 gene has homology to the catalytic domain of ras GAP (GTPase activating protein); called neurofibromin - keeps Ras in active GTP form
5) Perhaps only one copy needs to be mutated to give benign neurofibromas; but loss of second gene is required for malignancies
What is familial polyposis coli (FPC; A.K.A. Familial adenomatous polyposis coli (FAP))?
1) Colon - normal at birth; hundreds of small polyps form during first 20 years of life
2) Polyps are asymptomatic; significant risk of progression to colon cancer, approaching 100% by age 50
3) Autosomal dominant predisposition to colon cancer, highly penetrant (almost complete penetrance)
4) APC gene mutation - product controls the levels of a transcription factors Beta-catenin (and indirectly Myc)
5) Loss of APC genes is the first step in progression to cancer
How does Wnt normally stimulate cell proliferation?
1) Wnt binds to a cell membrane receptor
2) Binding signals APC to release from Beta-catenin destruction complex
3) Beta-catenin normally binds to intracellular portions of cadherins to stabilize them, but when it is released from APC, it will go to the nucleus to activate a transcription factor for cell proliferation
4) Beta catenin also prevents cells from piling on top of one another by regulating E-cadherins
What is the function of E-cadherin?
Glycoprotein that acts as glue between cells
What happens when APC is mutated?
1) When APC is mutated, the Beta-catenin destruction complex is no longer functional
2) Beta-catenin will continue to stimulate cell proliferation
Describe the progression of colon cancer
1) 2 APC mutations causes a nest of epithelial cells to grow on the basement membrane of the colon - this results in dysplasia (early)
2) 2 APC + 1 Kras + 2 SMAD mutations results in a break in the epithelium and an outward growth of a blood vessel with a nest of cells previously grown. This is called a polyp (intermediate)
3) More polyps begin to grow (late adenoma)
4) 2 APC + 1 Kras + 2 SMAD + 2 p53 mutations - Once polyps begin to spread their cells into the blood stream, the cancer becomes metastatic (carcinoma)
What is lynch syndrome (Hereditary nonpolyposis colon cancer (HNPCC))?
1) Colon cancer with fewer polyps, young age of onset; also other cancers
2) Autosomal dominant predisposition to cancer
3) Cells show microsatellite instability in tissue culture
4) Genes involved in repair of DNA sequence mismatches: hMSH2, hMLH1
5) Patients are susceptible to spontaneous mutations which contribute to multistep progression of cancer (Bulge mismatches can be created by misinsertion or strand slippage)
