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77 Cards in this Set

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What are the three major classes of receptor signals?
1) phosphorylation/ dephosphorylatin… 2) GTP/GDP exchange… 3) Acetylation/deacetylation (Post translational modification not a receptor signal)
Illustrate the phosphorylation pathway
Dephosphorylated substrate (inactive) --> Protein kinase w/ ATP --> (ADP byproduct) + Phosphorylated substrate (active) --> [interaction with effectors-AND/OR- Protein phosphatase] --> (Pi byproduct) + Dephosphorylated substate (inactive)
Name the 6 signaling pathways.
1) nuclear hormone receptors… 2) ligand-gated ion channels… 3) G protein coupled receptors (with second messenger c-AMP)… 4) Receptor protein tryosine kinase (RAS and MAP Kinase)… 5) cytokines receptor and non-receptor tyrosine kinase… 6) proteolysis regulated signals
Which of the signaling systems utilizes different domains with various functions as well as a basic plan?
Nuclear hormone receptors
Which cancers would be good candidates for nuclear hormone receptors?
breast, prostate, APL
Why are multiple waves of signaling seen in NHRs?
NHR's secondary response would be downstream gene activation
Do NHRs cause phosphorylation?
Not directly… indirectly through other activated gene products
What are the 4 classes of stimulating/inhibiting molecule that affect NHR activity?
antagonists, agonists, inverse agonists, partial agonists
Do Antagonists change the ratio (equilibrium)?
What are 3 ways to prevent hormone production?
1) remove organ… 2) chemical castration… 3) prevent biosynthesis
What is an LHRH agonist? What is its mechanism of action? What cancer is it used to treat?
It a method of chemical casatration to prevent the synthesis of hormones… it does it by desensitizing the system and thus shuts the system down… it used in prostate cancer
What is an aromatase inhibitor? What is its mechanism of action? What type of cancer is it used to treat?
It inhibits aromatase, which is an enzyme needed for estrogen and progesterone synthesis (found in fat cells.. Thus obesity is associagted with breast cancer)

Estrogen receptor positive
which three molecules used in preventing hormone binding to its receptors?
Receptor antagonists, partial agonists, anti-androgen,
What type of hormone interrupting drug is Tamoxifen… and what is it used for?
Receptor antagonist/partial
agonist… breast cancer... estrogen receptor positive
What type of hormone interrupting drug is Flutamide… and what is it used for?
pure antiadrogen/receptor antagonist… prostate
What is the role of 5-HT3 in cancer and how does it gain its selectivity?
5-HT3 is a serotonin ligand gated ion channel, which is related to nausea and vomiting… this receptor is unique when compared to other Serotonin receptors (Na and K)
Which receptor is a seven transmembrane protein? What is another name for this type of receptor?
G-protein coupled receptor… heptahelical receptor
What types of extracellular signals activate G-Protein coupled receptors?
Many: Sensory (light, tastes), ions, small peptides, proteins, and enzymes
Which cell signalling pathway accounts for 70% of all drug sales (including illegal) and 50% of legal drugs
Give the pathway for G-proteins.
G protein-GDP + GEF + GTP -(loss of GDP)-> G-protein-GTP -> [interaction with effectors -> leads to biological functions] --> G-protein-GTP +GAP -(loss of Pi)-> G-protein-GDP
What are the components of a GPCR?
Receptor, ß, ∂, (ligand that binds the receptor) and GTP or GDP
What is the GEF in GPCR?
the receptor
What binds the GTP in GPCR?
the Alpha subunit
Give the cAMP pathway in a GPCR.
G∂ --> Adenylyl cyclase + ATP --> 4-each cAMP + inactive PKA --> active PKA (catalytic subunits) enter nucleus and phosphorylate CREB (transcription factor)
What causes Kaposi's sarcoma? ... Which signal transduction pathway (receptor) is implicated in this disease? What is the direct result of this pathway somatick mutation?
Human herpesvirus 8 (HHV8), which contains GPCR with constitutive activity --> leads to angiogenosis
What clinical manifestations would arise from an HHV8 infected AIDS patient?
stimulation of angiogenosis --> neoplasms with highly vascular multiple cell types in the skin , lungs and the GI tract (including mouth)
In Kaposi's sarcoma, what two mechanisms is effected and as a result, what is released from the cells?
HHV8 constitutively activates the G-protein coupled receptor signaling pathway --> which leads to secretion of VEGF
Match the following: APL and CML… fusion of Bcr-to-ABL, PML-to-RAR… which requires a Flt3 mutation.
APL: PML-RAR (requires Flt3 mutation)… CML: Bcr-ABL
Name the receptor type: domains have a specific function
Name the receptor type: flt3
receptor protein tyrosine kinase
Name the receptor type: causes APL
RAR:nuclear hormone receptor… and Flt3: receptor tyrosine kinase
Name the receptor type: implicated in CML
non-tyrosine kinase: Bcr-ABL
Name the receptor type:Rx is retinoic acid
Name the receptor type: Gleevec is used as a Rx
ABL- non receptor kinase: Bcr-ABL philidelphia chromosome
Name the receptor type: blocked with agonists, antagonists, inverse agonist
Name the receptor type:5-HT3
ligand gated ion channel: serotonin
Name the receptor type: 7 transmembrane receptor
Name the receptor type: associated with scaffolds and signaling complexes
receptor protein tyrosine kinase
Name the receptor type: wide variety of activating signals
Name the receptor type: activated by dimerization
receptor protein tyrosine kinase… cytokine receptors, non-tyrosine kinase (src, Jak-STAT), ErbB2 (RTK example of heterodimers)
Name the receptor type: receptor acts as GEF
g-protein coupled receptor
Name the receptor type: associated with ErbB2
receptor protein tyrosine kinase
How does ErbB2 activate
What is the mechanism of action for Herceptin (ErbB2/Her2/neu?
mAb-Her2 (for receptor)... down-regulation or cytoxic mediated
What is the mechanism for Gleevec?
blocks the binding of ATP to Bcr-ABL
Name the receptor type: capable of autophosphorylation
receptor protein tyrosine kinase
Name the receptor type: utilizes the RAS MAP kinase pathway
tyrosine and non-tyrosine kinase pathways, including cytokine receptors
Name the receptor type: associated with proteolysis
Notch signaling
Name the receptor type: Jak-STAT and Src Kinase
non-tyrosine kinase
Name the receptor type: implicated in Acute lymphocytic leukemia (ALL)
Non-receptor kinase: Bcr-ABL philidelphia chromosome
What is the role of ABL in CML?
influences cell cycle vs. apoptosis
Which (ABL or Bcr) expresses src homology, DNA binding, and acting binding domains?
Which (ABL or Bcr) expresses kinase and dimerization domains (and GEF/GAP)?
What is Ki-1 lymphoma caused by?
fusion of NPM and ALK to produce a constitutively active protein
What type of receptor is Ki-1 lymphoma?
receptor protein tyrosine kinase
What is Ki-1 lymphoma (the fusion of proteins NPM and Alk) an example of?
bad scaffolding… thus it has abnormal distribution
Match the functions of NPM and ALK: Oligodimerizes, kinase, found in the nucleus
NPM: oligodimerizes + found in the nucleus… ALK: kinase
Name the receptor type: associated with erbB2 and Ki-1 lymphoma (NPM-ALK)
receptor protein tyrosine kinase
Name the receptor type and name: EGFR, heterodimerizing, no known ligand,
RTK, erbB2/HER2/neu
Who are the candidates for Herceptin? What is the strategy?
erbB2/HER2/neu… anti-mAB (which binds the receptor)
What are the 5 strategies for blocking RTKs?
1) bind ligand w/Ab… 2) soluble receptor… 3) block tyrosine kinase itself… 4) stimulate degradation of kinase… 5) block transcription factors
what are the 2 proposed mechanisms of Herceptin?
1) down regulates Her2/neu... 2) mAB works with cytoxic T-cells...
What are the side effects of herceptin?
Which chromosomes are Bcr and ABL found on?
bcr=22… abl=9
Which disease presents with high WBC, splengomegaly, fatigue and weight loss?
CML… bcr-ABL
Which translocation mutation leads to adhesion, mitogenesis, inhibition of apoptosis
Bcr-ABL: Ph chr...
AIM stripped toothpaste
What are possible causes of resistance to STI571? (Gleevec) Which is most likely?
increased BCR-ABL, pumpls, point mutations so that it no longer fits in cleft… point mutation in pocket
T/F: KSHV GPCR activate more than one signaling pathway
Name the 6 stages of angiogenesis
1. Endothelial cell activation
2. Basement membrane degradation
3. Endothelial cell imigration
4. Invasion of the ECM
5. Endothelial cell proliferation
6. New capillary tube formation
What 4 things can trigger angiogenesis?
1. tumor hypoxia
2. oncogenes
3. cytokines
4. cell growth factors
Give 5 reasons why angiogenesis is a good target for chemotherapy.
1. Endothelial cells are not malignant
2. Tumors require blood supply
3. Blood vessel density = tumor aggressiveness
4. Angiogenesis inhibition causes tumor regression in mice
5. Many standard chemo-drugs have anti-angiogenic properties
What are the two forms of Ab?
Cell surface Ab and soluble target Ab
Give 3 mechanisms used in antibody-based therapy.
1. Ab-Toxin
2. Ab --> activates immune system
3. Alter cell signalling:
- remove growth factor for circulation
- Clearing receptor from the cell
What type of toxicity is seen with Avastin? What is the mechanism of action for AV (BV)?
1. hypertention (nominal GI perforation)
2. Human mAb directed at VEGF
What is Avastin's (BV/AV) mechanism of action?
Anti-VEGF mAb
Name 4 anti-Angiogenic therapies in clinical trials.
1. Endogenously occuring inhibitors: a) Agiostatin... b) Endostatin
2. Inhibition of pro-angiogenic factors: VEGF (Avastin = anti-VEGF mAB)
3. IL-12: upregulates antagonists of KSHV-GPCR.
4. Thalidomide
What is the mechanism of pathology behing ErbB2/HER2/neu tumor models?
Two hits:
1. Gene amplification --> protein overexpression
2. Transformed cells only occur when overexpression of ErbB2/HER2/neu is accompanied by other EGFR overexpression