Term
| what are tumor suppressor genes known as? how many are there known? |
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Definition
| the brakes to cell proliferation, there are ~30 known |
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Term
| why are oncogenes thought of as dominant and tumor suppressor genes thought of as recessive? |
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Definition
| oncogenes are considered dominant, b/c if one allele is damaged, it overrides the normal allele whereas both tumor suppressor genes have to be damaged/knocked out for abnormal gene function to occur |
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Term
| how were tumor suppressor genes first observed? |
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Definition
| tumor suppressor genes were observed to either have one hereditary hit and a second somatic hit resulting in a loss of function or 2 somatic hits knocking out both alleles, also resulting in a loss of function (2 hit hypothesis) |
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Term
| what is haploinsufficiency? |
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Definition
| a phenomenon where tumor suppressors are not mutated, but their protein output is still reduced - resulting in cells still being pushed towards malignancy. |
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Term
| what do tumor suppressor genes code for? |
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Definition
| cellular protein components of the growth inhibitory pathways in the nucleus, cytosol, plasma membrane and cell surface |
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Term
| what is the retinoblastoma gene? how is it regulated? |
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Definition
| the Rb gene is the first tumor suppressor gene discovered. it keeps cells from going from G1 to S in its active/underphosphorylated state; if it is phosphorylated, Rb becomes inactivated and will allow the cell to go from G1->S. during the M phase pRb will again be dephosphorylated |
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Term
| what does Rb do specifically in its hypophosphorylated/active form that keeps the cell cycle from progressing? what happens if Rb is mutated? |
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Definition
| active Rb binds the E2F transcription factor along with DNA to inhibit S phase genes. if Rb is deleted/mutated it will stay phosphorylated and E2F will be released and bind to E2F responsive genes -> cell cycle is activated <- probably the most important break in cycle |
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Term
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Definition
| p53 is the key gene that monitors DNA synthesis after cell cycle arrest, allows for repair and will induce apoptosis if repair is not possible |
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Term
| what is the mechanism of p53 action? |
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Definition
| p53 inhibits DNA replication, helicase activity, pRb expression, and can induce apoptosis (xrays/chemotherapy can stimulate this) <- p53 is commonly found to be damaged in cancer |
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Term
| is there anything that regulates p53? |
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Definition
| Mdm2, a murine double minute oncogene protein can inactivate p53. p53 usually represses its transcription |
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Term
| can x rays/chemotherapy used to intentionally damage DNA activate normal p53? what is the expected result? |
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Definition
| yes this is a common anti-cancer therapy, and apoptosis should result |
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Term
| what is p21? is its gene induced by anything? when? |
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Definition
| p21 is a cyclin dependent kinase inhibitor at G1. p21 genes are induced by p53 in response to DNA damage |
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Term
| what is the correlation of mutations in p53 with esphageal cancer? |
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Definition
| esophageal cancer survival is much lower with p53 mutations |
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Term
| what are BRCA-1 and BRCA2? |
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Definition
| these are genes for DNA repair (either base pair deletions or point mutations) and bind proteins encoded by RAD51 to fix DNA |
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Term
| what can inherited mutations in BRCA-1 and BRCA2 lead to? germline mutation? |
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Definition
| mutations in BRCA-1 and BRCA2 can lead to development of breast, ovarian, colon and prostate cancer. germline mutation in BRCA-1 and BRCA2 can lead to development of epithelial ovarian CA |
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Term
| what is the link between BRCA-1 and BRCA2 mutations and breast CA? |
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Definition
| 5-10% of breast cancers are familial and 80% of these have BRCA-1 or BRCA-2 mutation |
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Term
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Definition
| the main function of APC (adenomatosis polyposis gene) is thought to be remaining bound to beta-catenin, which when not bound by APC, will move from the cytoplasm to the nucleus and act as a transcription factor |
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Term
| what are the MCRs on the APC gene? |
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Definition
| the MCRs (mutation cluster regions) on the APC gene are highly susceptible to change and lead to a truncated and improperly functioning APC |
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Term
| what can happen with a poorly-functioning APC? can this condition be inherited? |
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Definition
| germline mutations of APC (FAP - familial adenomatous polyposis) are possible and are typically found in GI polyps that start out benign and can become carcinomas, (GI is hit w/toxins constantly from food etc) |
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Term
| what is the NF-1 tumor suppressor gene? what does it do? |
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Definition
| the NF-1 tumor suppressor gene encodes a protein that binds to the ras protein and enhances its GTPase activity, (keeping it from remaining active and over stimulating the MAP-kinase pathway) |
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Term
| what can mutations in the NF-1 tumor suppressor gene lead to? what is a risk of pts with this? |
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Definition
| mutations in both alleles of the NF-1 tumor suppressor gene will give rise to benign neurofibromas, a condition called neurofibromatosis-1 which can lead to development of neurosarcomas. children with this have increased risk of AML |
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Term
| what does TGF-beta do? how is this action mediated? |
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Definition
| TGF-beta is mediated by Rb and can suppress c-myc activation by promotion of lead to promotion of proteins: p27,p15,p16 (these inhibit phosphorylation of Rb). (w/out Rb, c-myc is no longer downregulated and can run out of control) |
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Term
| what are some general characteristics of oncogenes? |
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Definition
| oncogenes in general promote activity for cell growth, they can be translocated, they are not usually hereditary, they are dominant (one damaged allele with dominate), they do not have tissue specificity (can be found in leukemias, lymphomas, and solid tumors) |
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Term
| what are some general characteristics of suppressor genes? |
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Definition
| suppressor genes often lead to inactivity of the system, these genes will often be deleted in tumors, they are hereditary, they are recessive (both alleles need to be deleted to lose functionality), and tumor suppressor genes are specific for solid tumors |
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Term
| what are anti-apoptotic genes? are they considered tumor suppressor genes? |
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Definition
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Term
| what are pro-apoptotic genes? |
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Definition
| bax, bad, bid, bcl-xS; which are not considered to be tumor suppressor genes |
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Term
| what do both bcl-2, bcl-xl AND bax, bad, bid, bcl-xS regulate? |
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Definition
| these govern mitochondrial membrane permeability and release or maintenance of cytochrome C. bax, bad, bid, bcl-xS are pro-apoptotic and activate release of cytochrome C through caspases 3 & 9 |
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Term
| what is the PTEN gene? is it commonly mutated? |
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Definition
| the PTEN gene codes for a phosphotase and tensin homolog which is a phosphoinositide that inactivates PI 3-kinase dependent signaling leading to inhibition of cellular proliferation, survival and growth. this gene, found on chromosome 10 is often mutated or deleted in normal cells (putting them at a higher cancer risk) |
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Term
| what do DNA repair genes have that are vital for DNA maintenance? what do they do? what is found to be the case with these if the DNA repir gene is abnormal? |
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Definition
| DNA microsatellites are repetitive triplet repeats of nucleotides (such as hMSH2, hMLH1, hPMS1, hPMS2) that are critical for DNA repair - they act as "spellcheckers" for basepair mismatches. they are found to be changed when the DNA repair gene is functioning abnormally -> leading to instability, which leads to deficient DNA mismatch repair processes |
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Term
| what are 2 cancers associated with DNA repair? |
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Definition
| xeroderma pigmentosum and HNPCC (Lynch Syndrome) |
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Term
| what is xeroderma pigmentosum? |
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Definition
| xeroderma pigmentosum is a cancer associated with defective DNA repair, leading to an increased risk of skin cancer w/UV exposure. specifically pyrimidines are crosslinked and prevent DNA replication due to a defect in nucleotide excision repair |
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Term
| what is HNPCC (lynch syndrome)? |
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Definition
| hereditary nonpolyposis colon cancer accounts for 2-4% of all colon CA, involves at least 4 mismatch repair genes and is associated with colon cancers in pts <50 yrs old |
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Term
| what are telomeres, what happens to them over time? what does telomerase do? |
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Definition
| telomeres are at the end of every chromosome and as we age, DNA is lost and the chromosomes shorten. telomerase adds TTAGGG segments to telomeres that have lost DNA |
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Term
| what is a potential problem with telomerase? |
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Definition
| telomerase can act in an abnormal way and put material back on the ends of chromosomes where it doesn't belong -> leading to newly structured genes and abnormal products |
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Term
| what cells have telomerase activity? |
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Definition
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Term
| do cancer cells have increased telomerase activity? |
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Definition
| yes, gastric, colorectal, lung, breast, prostatic cancers all have very high percent of telomerase activity. research is being done to figure out how to silence telomerase activity |
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