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43 Cards in this Set
- Front
- Back
What type of cancer will result from cells originating in (a) epithelial (b) mesenchymal (c) WBCs
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(a) carcinoma (b) sarcoma (c) leukemia/lymphoma
*carcinomas & sarcomas have solid tumors |
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What are the differences btw familial vs. sporadic cancer?
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Familial -- Involves germline and somatic mutations; multiple tumors, early onset, bilateral.
Sporadic -- Two somatic mutations; 1 tumor, later onset, unilateral. |
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What is the mechanism by which cigarette smoke causes DNA mutations?
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Polycyclic hydrocarbons (from smoke) converted to epoxides via aryl hydrocarbon hydroxylases (CYP) leading to DNA mutations (lung cancer).
(Note: enzyme is inducible and in pts w/hi-inducability allele will be more prone to CA) |
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What class of proto-oncogenes and what CA is caused by the following oncogenes
(a) Abl (b) Myc (c) Telomerase |
(a)cytoplasmic tyrosine kinase, CML (chronic myelogenous leukemia) *cell signaling
(b) transcription factor, Burkitt lymphoma *gene transcription (c) Telomerase, Many types of cancer * cell senescence |
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What translocation has been assoc. with Burkitt lymphoma?
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MYC proto-oncogene from chromosome 8 to 14 resulting in expression by promoter region of IG heavy chain genes.
t(8;14)(q24;q32) t(8;22)(q24;q11) t(2;8)(p12;q24) *characteristic B-cell tumors in Jaw- equatorial Africa |
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What chromosomal translocation is associated with CML (chronic myelogenous leukemia)?
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ABL proto-oncogene translocates from 9 to 22 and is joined by BCR resulting in inc. tyrosine kinase activity creating excess myeloid precursors.
t(9;22)(q34;q11) *altered 22 known as Philadelphia chromsome |
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Describe the mechanism of the following viruses in CA (a) HPV (b) HTLV-1
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(a) Viral proteins inactivate tumor suppressors Rb and p53 (b) Tax protein of virus is a coactivator for proto-oncogenes resulting in T cell leukemia
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Describe the mechanism of the following viruses in CA : HIV
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Tat transcription factor of the virus activates synthesis of cytokines promoting T cell proliferation and causing non-Hodgkin lymphoma
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Describe the 3 main proteins involved in the regulation of the cell cycle.
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1. Cyclins:
regulate cell cycle (proto-oncogene) Cyclins (inducible) must combine to cycline dependent kinases (constitutive) to become active. 2. Cyclin dependent kinases (CDKs): (constitutive, proto-oncogenes) 3. Cyclin dependent kinase inhibitors (CKIs): (inducible, tumor suppressors) bind to active complex (cyclin + CDK) to make it inactive |
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How do activated cyclin dependent kinases act on the cell?
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Phosphorylate retinoblastoma protein causing it to dissoc. from E2F transcription factor. Thus, E2F can cause cell cycle progression from G1 to S. Mutation of Rb leads to retinoblastoma.
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What is p53?
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It is a tumor suppresing transcription factor. p53 initiates transcription of repair enzymes and p21 (a CKI) leading to cell cycle arrest. Can also initiate apoptosis.
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What is the inheritance pattern and cause of Li-Fraumeni syndrome?
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Autosomal dominant. Caused by p53 mutations leading to many different cancers.
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What is neurofibromin (NF-1)?
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tumor suppressor that deactivates RAS by hydrolyzing GTP. (RAS is active in MAP kinase cascade).
Mutation in NF-1 can lead to neurofibromatosis. |
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What are cadherins and catenins? Specifically what is beta catenin?
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Cadherins - mediators in cell to cell contact (tumor suppressor).
Catenins - bind actin to cadherins. B catenin is also a transcription activator (proto-oncogene). |
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How is beta catenin usually regulated? What CA is assoc. with this regulation pathway?
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Inactive by being bound to cadherins and APC (adenomatous polyposis coli). APC mutations/deficiencies lead to familial polyposis colon CA.
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What pathologies are assoc. with RecQ BLM helicases?
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Bloom's syndrome.
Werner syndrome (premature aging). Rothmund-Thompson syndrome (skin abnormalities). |
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What are caspases?
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Cysteine proteases secreted as proenzymes (inactive) and activated by proteolytic cleavage to induce apoptosis.
-pro-apoptotic molecules (tumor suppressors) |
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What number caspases are initiators? Execution?
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8,9,10.
3,6,7. |
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What cascade occurs after mitochondria perceives death signals?
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Release of cytochrome C (CYM C) from mitochondria. Binds to apoptotic protease activating factor 1 (Apaf1) and activates capase 9.
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Name 3 anti-apoptotic proteins and describe their function.
(Bcl-2 family) |
BCL-2, BCL-X, BCL-W. Can bind and inactivate Apaf 1 and antagonize the actions of proapoptotic factors (BH3-only).
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Name 3 proapoptotic channel forming proteins and describe their function.
(Bcl-2 family) |
BAX, BAK, BOK. Form channels in outer mitochondrial membrane -- releasing CYM C. Dependent on binding of BH3-only (pro-apoptopic) members.
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Name 3 pro-apoptotic BH-3 only proteins and describe their function.
(Bcl-2 family) |
BAD, BID, BIM. Regulate anti and channel-forming proapoptotic factors.
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What translocation is involved in follicular B cell lymphoma?
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BCL-2 translocation from 18 to 14 and places it under promoter control of IG heavy chain genes. Elevated BCL-2 proteins lead to dex. cell death and lymphoma.
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Benign vs malignant tumors
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benign tumors- a tissue w/ abnormally high cell number (neoplasm), do not have invasive properties, genetic/epigenetic transformation of normal cells
malignant (cancer) tumors- invades other tissues (metastasize) *all tumors formed by increased cell formation or decreased cell death |
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Define oncogenes
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overactivated proto-oncogenes
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Define proto-oncongenes
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induce cell growth or proliferation
inhibit cell death (anti-apoptotic) increase cell number gain-of-function mutations (overactivation), generally, one mutated allele |
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Define tumor suppressors
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inhibit cell growth or proliferation
induce cell death (pro-apoptotic) decrease cell number loss-of-function mutations (inactivation) both alleles must be mutated |
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How are proto-oncogens get converted to oncogenes?
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-Radiation or chemical carcinogen causes mutation in coding and/or promoter region causing production of hyperactive protein and excessive expression of proto-oncogene
-gene rearrangement occurs, proto-oncogene is under control of strong promoter/enhancer -proto-oncogene fused w/ another gene -fusion protein is either overproduced or hyperactive |
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Viral oncogenes associated w/ cancerous transformation of cells
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Papilloma virus-
proteins inactivate tumor suppressors RB & p53 causes cervical cancer HTLV-1- Tax protein is a coactivator of proto-oncogenes HIV- Tat transcription factor activates cytokine synthesis, promoting T-cell proliferation causes non-Hodgkin lymphoma |
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2 main pathways of apoptosis
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1. death receptor pathway
2. mitochondrial pathway -both eventually activate the caspase cascade inside cell -chromatin condenses, DNA fragments, cell shrinks & breaks into apoptotic bodies, bodies cleared out by macrophages |
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How is Bcl-2 activated in follicular B-cell lymphoma
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-translocation moves Bcl-2 from chromosome 18 to 14 & places it under promoter control of immunoglobin heavy chain genes
-elevated Bcl-2 prevents death of B cells which leads to massive B-cell expansion=lymphoma t(14;18)(q32;q21) chromosomal translocation |
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Sources of the second hit in hereditary tumors (3)
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1. loss of heterozygosity
-loss of entire normal gene, deletion, non-disjunction, abnormal recombination 2. loss-of-function mutation -in the normal allele, compound heterozygosity 3. epigenetic silencing -of the normal allele |
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Causes of mutations (3)
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1. carcinogens
2. radiation 3. UV-light |
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what are carcinogens and what do they do?
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-chemicals that irreversibly modify DNA structure, usually metabolized in the human body first, modify DNA chem. structure
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How is G1/S transition controlled?
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Binding of cyclins activates the kinase activity of CDKs.
E2F (transcription factor, proto-oncogene) and Rb (retinoblastoma protein, tumor suppressor) are seperated by activated CDK complex. E2F goes on the increase gene transcription & cell-cycle progression |
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What is the two-hit hypothesis?
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for inactivation of tumor-suppressor genes
-first hit: germline mutation + somatic mutation (familial) or somatic mutation + somatic mutation (sporadic) -second hit: loss of heterozygosity or loss-of-function mutation or epigenetic silencing of normal allele |
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What tumor suppressor gene class and protein are the following diseases associated with?
-Stomach cancer -Neurofibrosarcoma -Retinoblastoma, sarcomas -most cancers -breast cancer |
-stomach cancer: adhesion protein receptor. E-cadherin
-Neurofibrosarcoma: signal transduction, NF-1 -Retinoblastoma, sarcomas: transcription factor cell-cycle regulation, Retinoblastoma -Most cancers: cell cycle/apoptosis, p53 -Breast cancer: DNA repair, BRACA 1 |
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What does retinoblastoma protein do normally?
What do mutation in the protein lead to? |
Retinoblastoma protein regulates the transmission from G1 to S phase
Mutations lead to retinoblastoma (retina cancer) |
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What is a characteristic feature of retinoblastoma?
Is it a heritable or sporadic cancer? |
white reflection of the retina
the cancer has both heritable and sporadic form |
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What does p53 do?
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p53 allows cell to undergo apoptosis if damage/stress is too great, or arrests the cell cycle until repair/correction is made if damage/stress is not too great
*mutation in p53 pathway almost always present in cancer |
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Difference btwn initiator & execution caspases
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initiator (8,9,10)
-activated directly by the death cell receptor & mitochondrial pathways execution (3, 6, 7) -activated by initiator caspases -cleave many diff proteins in cell, including actin, proteins of nuclear envelope, DNA repair enzymes & the inhibitor of caspase dependent endonuclease |
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How is apoptosis regulated?
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depends on ratio of pro-apoptotic and anti-apoptotic molecules
-when pro-apoptotic molecules increase, more pro-apoptotic channel are functional, increasing CYM C release |
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What does the formation of sporadic cancer require?
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multiple de novo mutations in diff oncogenes and/or tumor suppressor genes
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