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68 Cards in this Set
- Front
- Back
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What 3 domains are present on all nuclear receptors? |
1. Ligand binding 2. Central DNA-binding (zinc fingers) 3. Variable |
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Type I nuclear receptors: Bind what type of hormones? Bind what type of DNA? What type of dimer? Where are they found/bound to what? |
Steroid hormones Inverted repeats Homodimer Found in cytoplasm bound to HSP |
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Type II nuclear receptors: Bind what type of hormones? Bind what type of DNA? What type of dimer? Where are they found/bound to what? |
Vit D, Retinoic acid, Thyroxine Direct repeats Heterodimer w/ RXR Found in nucleus |
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What drug is used to treat ER (+) breast cancers? How does it work? Side effects? |
Tamoxifen -Binds to the ER and prevents interactions with coactivators -Increased risk of uterine cancer |
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What do prostate stromal cells produce? Epithelial cells? Which express the androgen receptor? |
Stroma: growth & survival factors Epithelial: PSA Both express AR |
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What drugs are used to treat prostate cancer by inhibiting testosterone production from the testes? How do they work? |
Lupron & Zoladex LHRH agonists that cause chemical castration |
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What drugs are used to treat prostate cancer by inhibiting androgens produced by the adrenal cortex? How do they work? |
Flutamide & Casodex Androgen antagonists that block AR signaling |
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What are the mechanisms that can explain hormone-refractive cancer? (4) |
1. Cross-talk between signaling pathways 2. Selective activation of an alternative pathway 3. Mutations in the receptor 4. Over-expression of receptor or coactivators, under-expression of cosuppressors |
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What are the 3 general categories of 'other' mechanisms of signal transduction? |
1. Cytosolic multi protein complex signaling 2. Signaling involving proteolysis 3. PI derivative signaling |
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In the Wnt pathway: What is the receptor? The txn factor? What activates the txn factor? Co txn factor? |
Receptor: Frizzled Txn factor: B-catenin Activated by: release from Axin, dephosphorylated Co txn factor: TCF |
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In the Hedgehog pathway: What is the receptor? The txn factor? What activates the txn factor? Co txn factor? |
Receptor: Patched Txn factor: Ci Activated by: Smo goes to membrane while Patched is sequestered, Ci dephosphyorylated, not cleaved to Ci75 Co txn factor: CBP |
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The NFkB pathway is involved in response to what? What protein is degraded? How? |
Stress I-kBa is phosphorylated by I-kB kinase, and destined for ubiquitin mediated protein degradation |
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The Notch pathway is involved in signaling between what kinds of cells? |
Neighboring cells |
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What is Notch's binding partner? What 2 proteins cleave Notch, and where? |
Delta Extracellularly: MMP (ADAM10) Intracellularly: y-Secretase (Presinilin 1) |
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What important signaling ligands are liberated by MMPs? |
EGF, Heparin-binding EGF, TGFa |
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What, other than a GPCR, can activate PLC? |
RTKs and cytokine receptors |
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What does PI-3 kinase act on? Downstream effectors? Results of pathway? |
PI derivatives (ie, PI 4-phosphate and PI 4,5-bisphosphate) Activation of PKB Cell division/survival |
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Describe the details of the activation of PKB & downstream effects (5) |
1. PKB exists in cytosol 2. PH domain on PKB binds to PI-3 derivatives 3. PKB is localized to the membrane and partially activated 4. PKB is further activated by PDK1 and PDK2 5. PKB goes back to cytosol and inactivates pro-aptotic proteins and Forkhead TFs |
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How is PKB involved in glucose metabolism? (3) |
Promotes glucose uptake and storage The IR is an RTK, which activates PKB Also phosphorylates Glycogen Synthase Kinase 3, to activate glycogen synthesis |
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What protein removes phosphates from PI-3 derivatives & counteracts PKB? (tumor supressor) |
PTEN |
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What three proteins are involved in cholesterol homeostasis? What are their roles? |
1. SREBP (txn factor that activates cholesterol biosynthesis genes) 2. SCAP (promotes cleavage of SREBP into its active TF form) 3. Insig-1 (inhibits SCAP) |
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Where are SREBP and SCAP when active? When inactive? |
Active: Golgi (/nucleus) Inactive: ER |
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What is the most important enzyme in cholesterol synthesis? |
HMG-CoA Reductase |
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What is the building block of cholesterol (2C)? 5C intermediate? 10C intermediate? 15C intermediate? 30C intermediate?
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2C: acetyl-CoA 5C: isoprene 10C: geranyl pyrophosphate 15C: farnesyl pyrophosphate 30C: squalene |
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What is the overall HMG-CoA reductase reaction? |
3 Acetate + NADPH -> Mevalonate + NADP+ |
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What, other than cholesterol, can be synthesized from activated isoprene? (3) |
1. Quinone electron carriers 2. Dolichol (involved in glycosylation) 3. Lipid soluble vitamins K, E, A |
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What kind of enzymes close the rings in squalene? |
Monooxygenases |
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What pathway is involved in cholesterol-sensitive expression of HMG-CoA reductase? What is the DNA binding region? |
SREBP/SCAP/Insig SRE (Sterol Reg Element) |
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What proteins control the phosphorylation and dephosphorylation of HMG-CoA reductase? In which state is the reductase active? |
Reductase active when unphosphorylated Phosphorylation: AMPK Dephos: Phosphoprotein phosphatase |
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What is the enzyme that esterifies cholesterol? |
LCAT |
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What are the effects of glucocorticoids / Dexamethasone on metabolism in the liver? In the adipose? |
Liver: activates PEPCK -> increases in gluconeogenesis and glyceroneogenesis, export of TGs
Adipose: inhibition of PEPCK, FAs not taken up to be stored as TGs (no glycerol backbone), high plasma FAs |
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What glucocorticoid-derived drug is used to treat diabetes? How does it work? |
Thiazolidinediones (Rosiglitazone) Activates PEPCK in the adipose through nuclear receptor PPARy. This takes FAs out of blood to store in adipose, which helps improve insulin sensitivity. |
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What is a normal A1C? Prediabetic? Diabetic?
What is normal fasting glucose? Prediabetic? Diabetic? |
<5.5, 5.6-6.4, >6.5
<110, 110-125, >125 |
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What is measured to confirm DKA? |
Plasma acetone and B-hydroxybutyrate |
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LPL is active in adipose in what conditions? HSL? |
LPL: fed HSL: fasting |
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What causes the diabetic ketoacidosis in T1D? |
Uncontrolled activity of HSL in adipose frees up lots of FAs, which are transported to the liver and oxidized to acetyl CoA. This acetyl CoA is converted to ketone bodies. |
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Which has a higher mortality rate, DKA or hyperosmolar hyperglycemic nonketoic coma? |
HHNC |
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What diabetes-related visual impairment involves advanced glycation end products and increased sorbitol? |
Cataracts |
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What diabetes-related visual impairment involves increased eye pressure? |
Glaucoma |
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What diabetes-related visual impairment is first seen as retinal aneurysms that appear as red dots that disappear over time? |
Background retinopathy |
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What diabetes-related visual impairment involves neo-vascularization that causes loss of vision & is associated with retinal detachment? |
Proliferative retinopathy |
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Otitis extema is... |
recurrent fungal infections of outer ear canal, also under toenails or between toes |
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Necrobiosis lipoidica is..... |
reddish brown patches around shins and ankles |
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Acanthosis nigricans is.... |
An increase in pigmentation on the back of the neck and armpits |
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What class of drugs inactivates brush border enzymes and glucose transport?
What class of drugs mimics a GI hormone? |
a-Glucosidase inihbitors
GLP1-agonists |
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What is the mechanism of biguanides in treating diabetes? Common example? |
Increase RTK activity (insulin sensitivity) Metformin |
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What is the mechanism of Thiazolidinediones? |
PPARy activator that increases TG uptake by adipose |
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What is the mechanism of sulfonylureas and meglitinides? Which is short-acting? |
Increase insulin secretion from beta cells Meglitinides are shorter acting |
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What kind of enzymes modify cholesterol? Cofactor? |
Monooxygenases Cofactor: NADPH |
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Where is estrogen produced vs. progesterone (within the ovary)? |
Estrogen: granulosa cells & corpus luteum Progesterone: corpus luteum |
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What are the 5 classes of steroid hormones? How many carbons? |
1. Progestins (21C) 2. Androgens (19C) 3. Estrogens (18C) 4. Glucocorticoids (21C) 5. Mineralocortocoids (21C) |
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What is the first step in steroid hormone synthesis? (cholesterol -> ...) Why is it important?
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Cholesterol -> pregnenolone via P450/desmolase
Rate-limiting step |
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What enzyme is responsible for pregnenolone -> progesterone? |
3-B-hydroxysteroid dehydrogenase (3-B-HSD) |
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What are the signs of 3-B-HSD deficiency? |
Excessive Na+ excretion, ambigiuous genitalia in males, clitoromegaly in females |
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What enzyme is responsible for pregnenolone -> DHEA? What enzyme is responsible for DHEA -> androstenedione? What enzyme is responsible for androstenedione -> testosterone |
17a-hydroxylase (and 17,20 lyase) 3-B-HSD C17 dehydrogenase |
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What 2 reactions are carried out by aromatase in the granulose cells? |
Testosterone -> estradiol Androstenedione -> estrone |
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What is the best type of drug for treating post-menopausal women with breast cancer? |
Aromatase inhibitors |
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What is the principal site of estrone production? |
Adipose and skeletal muscle |
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What enzyme is responsible for progesterone -> 11-deoxycorticosterone (DOC) ? 11-deoxycorticosterone -> corticosterone? |
21a-hydroxylase 11B-hydroxylase |
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What is the final reaction in synthesis of aldosterone? |
Corticosterone -> aldosterone by aldosterone synthase |
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What enzyme is responsible for progesterone -> 17a-hydroxyprogesterone? 17a-hydroxyprogesterone -> 11-deoxycortisol? 11-deoxycortisol -> cortisol? |
17a-hydroxylase 21-hydroxylase 11B-hydroxylase |
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What results from 17a-hydroxylase deficiency? Symptoms? |
No sex hormones or cortisol are produced -Hypertension -Female-like genitalia |
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What results from 21a-hydroxylase deficiency? Symptoms? |
No mineralocorticoids or glucocorticoids are produced -Masculinization of genitalia in females, early virilization in males |
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What results from 11B-hydroxylase deficiency? Symptoms? |
No cortisol, aldosterone, corticosterone -Low-renin hypertension (due to deoxycorticosterone) -Masculinization of genitalia in females, early virilization in males |
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What is Vit D3 derived from (first step in synthesis)? |
7-dehydrocholesterol |
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What activates the last step of Vit D synthesis? Inhibits? |
Stim: PTH Inhibits: D3 & high extracellular Ca++ |
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What enzyme is deficient in Smith-Lemli-Opitz Syndrome? |
7-dehydrocholesterol reductase |
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What enzyme is deficient in Desmosterolosis? |
24-DHCR |
