Genetics-Cancer Genes Flashcards
Mutation in sporadic retinoblastoma vs. familial retinoblastoma
In sporadic event, the same mutation has to happen 2x to each chromosome in the same cell. In familial, you inherit on diseased allele and just need a second hit in any other cell. Note that familial form is most often bilateral.
Causes of second hit mutations in retinoblastoma
Loss of chromosome 13 due to cell division error, independent mutation in Rb gene, mitotic crossover and loss of chromosome with reproduction of disease allele.
Why is p53 the “guardian” of the genome that maintains genome stability?
Cell senses DNA damage -> p53 levels increase -> p21 transcription (CDK inhibitor inhibits G1->S transition), transcription of GADD45 (DNA repair enzyme) and promotes cell apoptosis.
Why is p53 mutation so prone to allowing for retinoblastoma?
DNA damage -> p53 transcription factor doesn’t activate -> p21 CDK inhibitor not transcribed -> CDK-cyclin remains active -> RB1 phosphorylated -> dissociates from E2F -> E2F translates mRNAs encoding enzymes for DNA synthesis -> cell proliferation. Note that both RB1 and p53 are tumor suppressors in this cycle.
How can HPV cause cervical cancer?
The viral protein E7 binds RB and frees E2F, allowing for cell proliferation. The viral protein E6 binds and inactivates p53 so the cell cannot repair DNA or promote apoptosis.
What role do BRCA1 and BRCA2 mutations have in increasing risk for breast cancer?
BRCA1 is necessary for signaling response to DNA damage. BRCA2 is involved in DNA repair. Mutations in these allows for lots of other mutations.
Why is APC associated with familial adenomatous polyposis related colon cancer?
It is the trigger in the adenoma carcinoma sequence. Its domains binds beta-catenin (decreases transcription for mitosis) and microtubules (affects mitosis and genome stability). Ironically aneuploidy can cause loss of tumor suppressor genes.
How many mutations do you usually need to activate an oncogene? To inactivated a tumor suppressor gene?
Oncogene: one dominant mutation. Tumor suppressor inactivation: two hit mutation (common in familial diseases)
What signaling pathway do cancer cells not have which results in them not arresting in G1 and piling on top of each other in a petri dish?
Absence of contact inhibition.
How is Burkitt lymphoma a product of oncogene expression?
t(8;14) puts the Ig promotor next to the c-myc protoncogene and c-myc gets over expressed
How is CML a product of oncogene expression?
t(9;22) puts the BCR-ABL next to each other and makes a constitutively active tyrosine kinase. This is why you can treat with Gleevec, a tyrosine kinase inhibitor.
Why is raf a potent oncogene?
Ras is activated by GEF (guanine nucleotide exchanging factor) that adds GTP -> Raf is activated -> MEK is phosphorylated -> MAP kinase is phosphorylated -> cell proliferation occurs. Ras is inactivated by GAP (GTPase activating protein). Mutations that lock raw in the GTP-bound form promote tumor growth.
What cyclin is activated by growth factors?
Growth factor binds -> Ras/Raf signaling -> Induces Cyclin D -> Cyclin D binds Cdk4/6 -> Rb is phosphorylated & deactivated -> E2F is freed and activated -> Gene transcription takes place -> Cell proliferation
How are CDKs regulated?
Phosphorylation, degradation, synthesis and inhibition
Knudson hypothesis
Multiple hits to DNA are required to cause cancer
