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56 Cards in this Set
- Front
- Back
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What are the main differences in the characteristics of benign and cancerous (malignant) tumors?
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Malignant:
uncontrolled growth metastasize invade local tissue life threatening Benign: uncontrolled growth do not metastasize do not invade local tissue not life threatening unless in confined space |
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What are 3 general ways in which cancer can be induced?
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1. Chemical carcinogens
2. irradiation by x-rays, UV light 3. viruses |
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Direct carcinogen
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act directly on a target molecule (nitrogen mustard)
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procarcinogen
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must be activated by prior metabolism to become carcinogens
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proximate carcinogen
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intermediate compounds along activation route of procarcinogens
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ultimate carcinogen
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final compound along activation route
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initiator
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substance that modifies DNA resulting in a mutation
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- promoter
- ex of common promoters |
- acts after initiator to carry the process through to malignant tumors
- saccharin and phenobarbital |
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Point mutation
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one base pain replaces another
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transition
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one purine or pyrimidine replaces another
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transversion
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a purine is replace by a pyrimidine and vice versa
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insertion/deletion
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one or more nucleotide base pairs is inserted or removed from DNA
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Ames Test
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a special strain of salmonella typhimurium that does not make histidine (and no LPS coat) is placed in a culture plate w/o histidine in the medium
- suspected mutagen placed in medium as well - The # of colonies that mutate back to the His+ phenotype is 2 days minus the control equals mutagenesis score |
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Approximately what percentages of cancers are caused by viruses and chemical carcinogens?
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80% by chemical carcinogens
15% by viruses |
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What are 4 major human tumor viruses?
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1. Epstein Barr virus
2. Hep B 3. HPV 4. Human T cell leukemia |
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What types of cancer does Epstein Barr induce?
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1. Burkitt's lymphoma
2. B cell lymphoma 3. nasopharyngeal cancer |
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What types of cancer does Hep B induce?
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hepatocellular carcinoma
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What types of cancer does HPV induce?
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genital and other tumors
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What types of cancer does human T cell leukemia induce?
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1. lymphoma virus 1 - adult T cell leukemia
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What are the 4 genes on the Rous Sarcoma virus, and what do they code for?
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1. Gag - core protein
2. Pol - reverse transcriptase 3. env - envelope protein 4. v-src - mediates host cell transformation (oncogene) |
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Name 5 chemical carcinogens
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1. alkylating agents
2. polycyclic aromatic compounds 3. nitrosamine 4. aromatic amines 5. naturally occurring compounds - aflatoxin B, arsenic, asbestos, beryllium, cadmium |
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What are the stages of the cell division cycle for eukaryotic somatic cells?
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G1 (growth)
S (synthesis of DNA) G2 (growth) M (mitosis Some cells have quiescent state G0 |
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In general terms, what are some of the things that cells must do in order to reproduce?
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1. increase in size
2. synthesize proteins, DNA, RNA and organelles 3. form and segregate new chromosomes 4. control and surveil process carefully 5. produce daughter cells |
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The formation, activation and deactivation of what components exert major control over the cell cycle?
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- specific protein kinases
- cyclins (protein kinase protein regulators) - kinase inhibitors - specific phosphoprotein phosphatases |
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What are 2 key timing decisions that are made as the cell cycle progresses?
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1. when to enter S-phase
2. when to enter mitosis |
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What are cyclins?
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protein regulators of the protein kinases
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What do cyclins control?
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Major changes that take place in the cell architecture such as the breakdown of the nuclear envelope, the condensation of chromatin, and extensive reorganization of the cytoskeleton.
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About how many cyclins are known?
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At least 12 have been identified
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What does the binding of cyclin A do to the cdK2 kinase?
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Causes a conformational change in cdK2, making the substrate-binding site properly aligned for activity
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What is the maturation promoting factor composed of?
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Made up of cyclin B and cdK2
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What cellular components does MPF modify?
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1. Proteins that initiate mitosis
2. laminins (filamentous proteins) causing nuclear envelope to break down 3. tubulin causing the microtubule organization to form the mitotic spindle 4. histone H1 to cause condensation of chromatin 5. proteolytic enzyme that causes clearage of cyclin B |
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How is MPF activated?
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phosphatase (cdc25) removing a phosphate from tyrosine-16
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How is MPF deactivated?
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Cycline B is cleared and ubiquitinated, which leads to complete proteolytic destruction of the cyclin and disintegration of the MPF complex
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What are the 2 major suppressor genes that have an effect upon cell division cycle?
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1. p53
2. Rb |
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What are the 4 major classes of proteolytic enzymes?
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1. Serine
2. Thiol 3. Zinc 4. Aspartyl |
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To what does plasminogen bind?
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1. fibrin
2. fibrinogen |
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Where is plasminogen located in respect to clots?
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It becomes incorporated into clots as they form
How: -- plasmin has 5 kringle domains on its amino terminus end -- fibrin also has two of these structures -- these structures aid in binding of plasminogen to fibrin **Plasminogen --> plasmin (activated form) |
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Name 3 compounds that activate plasminogen.
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1. tissue plasminogen activator (TPA)
2. urokinase 3. streptokinase |
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Briefly describe TPA
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- *** major activator ***
- 68 kD single chain protein - synthesized in endothelial cells following damage to vessels - finger domain similar to that found in fibronectin - region near amino-terminus homologous to epidermal growth factor - 2 kringle domains homologous to plasminogen - serine protese domain toward carboxy terminus |
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How does TPA work?
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1. binds to fibrin
2. becomes activated and cleaves plasminogen (in the clot) to give plasmin 3. plasmin cleaves clot to soluble products - TPA nor plasmin remain bound to soluble products - inactivated by natural inhibitors (alpha-2-antiplasmin) |
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Briefly describe urokinase
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- 55 kD serine protease found in urine
- readily activates plasminogen in absence of fibrin - contains kringle structure in amino-terminal region - secreted by epithelial cells lining renal tubules - a.a. sequence completely different from TPA |
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Describe the activity of urokinase
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Believed to be involved in lysing fibrin deposits in renal tubules
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Briefly describe streptokinase
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- 48 kD protein isolated from streptococci
- not a serine protease - forms 1:1 complex w/ plasminogen allowing proteolytic activity to be expressed - activates plasminogen in fluid phase where it degrades circulating fibrinogen and activate other plasminogen molecules |
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How does the method by which streptokinase functions differ from the ways urokinase and TPA function?
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- urokinase and TPA break the Arg-Val bond in plasminogen
- streptokinase, on the other hand, does not activate plasminogen by breaking its both; rather, it forms a 1:1 complex with plasminogen, allowing for the proteolytic activity to be expressed |
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Describe ubiquitination
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- ubiquitination is the tagging of abnormal proteins in the cytosol w/ ubiquitin (a small protein)
- tagging w/ ubiquitin leads to degradation of the protein |
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Describe the ATP dependent process of protein targeting involving ubiquitin.
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- the initial step required ATP:
[ubiquitin]-COO- --(1)--> [ubiquitin]-CO-S-E1 (1) in: E1-SH + ATP; out: AMP + PP1 - after a few more steps w/ different enzymes, the carboxy-terminal glycine of ubiquitin (NH), covalently attaches to the epsilon-amino group of lysine (Lys) residues of protein that will be degraded: [ubiquitin]-CO-NH-Lys-Protein **(refer to proteolysis packet p. 3 for full rxn) |
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- What determines the half-life of proteins in tissue?
- What are the 3 categories? |
- amino-terminal residue
- stabilizing, destabilizing, and highly destabilizing residues |
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Give examples of stabilizing residues
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Met, Gly, Ala, Ser, Thre, Val
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Give examples of destabilizing residues
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Tyr, Gln, Pro, Iso, Glu
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Give examples of highly destabilizing residues.
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Leu, Phe, Asp, Lys, Arg
**these favor rapid ubiquitinization |
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What is the means of protein target recognition for degradation of serum proteins?
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Loss of sialic acid residue from non-reducing end of oligosaccharide chains marks protein for degradation
--recognized by liver and degraded in lysozymes by cathepsins (protease) |
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How are plasminogen activators used in therapy?
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- Can be used in thrombolyric therapy to restore patency of coronary arteries after thrombosis
- if given early, can preserve the fnxn of occluded myocardium and reduce mortality |
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What type of complication can occur with plasminogen activators used in therapy?
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In addition to lysing the thrombus, hemostatic plugs can also be lysed -> cause complications, like bleeding
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What roles do proteases play in the pathogenic process in cancer?
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Tumors often secrete matrix metallo-proteases -- these break down blood vessel walls and extracellular matrix to allow tumor cell to metastasize
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What role do they play in AIDS?
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A viral protease (from aspartyl protease family of proteases) must cleave polyprotein structures in order for infected cells to spread virions
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What kinds of protease inhibitors are used for AIDS therapy?
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specific aspartyl protease inhibitors:
1. Sequinovir 2. Ritonavir |
