Myers Flashcards

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julieaburch
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Myers Flashcards
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2011-04-17 14:10:53
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  1. What three biological processes do Androgens (Testes) regulate?
    • Spermatogenesis
    • Maintenance of secondary sex glands, organs
    • Male secondary sex characteristics (eg male musculature)
  2. What three biological processes do Estrogens (Ovary, Placenta) regulate?
    • Oocyte maturation, Ovulation
    • Fertilization, Uterine Function
    • Female secondary sex characteristics (eg Mammary development)
  3. What two biological processes does Progesterone (ovary and placenta) regulate?
    • Ovulation
    • Fertilization, Uterine Function, Pregnancy Maintenance
  4. What four biological processes do Glucocorticoids (cortisol, adrenal cortex) regulate?
    • Glucose homeostasis
    • Immune modulation
    • Inflammation regulation
    • Blood pressure modulation
  5. What two biological processes do Mineralocorticoids (aldosterone, adrenal cortex) regulate?
    • Sodium homeostasis via kidney function
    • Water volume, blood pressure
  6. All steroid hormones are derived from what molecule?
    Cholesterol
  7. Where are cholesterol esters stored? How are they taken up by steroidogenic tissues? How are they liberated?
    • LDLs
    • Via LDL receptor, endocytosis
    • Liberated from fatty acid via Hormone Sensitive Lipase (cholesterol esterase)
  8. What is a secondary source of cholesterol?
    De novo synthesis from acetate in steroidogenic cells
  9. Where does Esterification occur on the cholesterol ring?
    At the three position
  10. What does Esterification do?
    Increases solubility of cholesterol
  11. What is the first rate limiting step in steroid hormone formation? What protein allows this step to happen?
    • Transport of cholesterol to the inner mito membrane
    • Steroidogenic Acute Regulatory Protein (StAR) binds to and transports cholesterol to the IMM
  12. What is the first rate limiting ENZYMATIC step of steroid hormone formation? What mediates this step? What is the resulting steroid precursor?
    • Cholesterol side chain cleavage (removal of C22-27 C chain
    • Mediated via Cytochrome P450 side chain cleavage
    • Pregenolone: not biologically active, but is the precursor for ALL steroids, committed fate
  13. Unlike cholesterol, Pregnenolone has greater _________ and can permeate the IMM and OMM and diffuse throughout the cell
    Solubility
  14. Is progesterone a biologically active steroid?
    Yes, but it can also serve as a precursor for downstream steroids
  15. Post-ovulation, what is the major female circulating hormone?
    Progesterone
  16. Are 17-alpha hydroxypregnenolone and 17-alpha hydroxyprogesterone biologically active?
    • Both are intermediate precursors to downstream steroid hormones, largerly devoid of biological activity, or weakly active.
    • However, they are/were being used in women during preterm labor to prevent premature births
  17. Biologically, what is the most active glucocorticoid in humans?
    Cortisol
  18. What is the target organ of glucocorticoids? What do they regulate?
    • Kidney (Adrenal Corticosteroids)
    • Regulate Sodium Homeostasis
  19. All members of the CYPC11 family are _________ enzymes.
    Mitochondrial
  20. The conversion of 17-alpha hydroxypregnenolone to DHEA via P450C17 lyase activity is dependent on what two things?
    • Presence of the chaperone protein -- CYPB5
    • Lack of expression of other enzymes that use 17-alpha hydroxyprogesterone as a substrate
  21. What is the main male androgen?
    Testosterone
  22. When do DHEA levels begin to drop in males?
    Around age 50
  23. What is the most biologically active Estrogen?
    Estradiol
  24. What are the three Mineralocorticoids? Are they weak or strong biologically?
    • Aldosterone: strong
    • Corticosterone: weak
    • 11-Deoxycorticosterone: weak
  25. What are the three Glucocorticoids? Classify them as biologically weak or strong?
    • Cortisol: strong
    • Corticosterone: weak
    • Cortisone: weak
  26. What are the five Androgens? Classify them as weak or strong.
    • Testosterone: strong
    • 5-alpha dihydrotestosterone: strong
    • DHEA: weak
    • Androstenedione: weak
    • Androstenediol: weak
  27. What is the most potent of all androgens?
    5-alpha dihydrotestosterone
  28. What are the three Estrogens? Classify them as biologically weak or strong.
    • Estradiol: strong
    • Estrone: weak
    • Estriol: weak
  29. 5-alpha dihydrotestosterone (5-alpha DHT) plays a critical role developmentally in males. What happens to males born with a defect or deficiency in this androgen?
    Born Amiguous
  30. How can cortisol be converted to coritsone? What does this do?
    • Converted by 11-beta HSD type II
    • Inactivates Cortisol expressed in kidney --> allows kidney to respond to aldosterone
  31. How can Progesterone be converted to 20-alpha dihydroprogesterone? How can it be converted to 5-alpha dihydroprogesterone? What do these forms do, and where are they important?
    • 20-alpha HSD
    • 5-alpha HSD
    • Inactive progestives --> important in uterus
  32. In circulation, steroid hormones are largely bound (95-99%) by binding globulins. What is the specific binding globulin for Estradiol and Testosterone?
    Sex Steroid Binding Globulin (STBG)
  33. In circulation, steroid hormones are largely bound (95-99%) by binding globulins. What is the specific binding globulin for Progesterone, Gluco- & Mineralocorticoids?
    Transcortin (Corticosteroid Binding Globulin; CBG)
  34. In circulation, steroid hormones are largely bound (95-99%) by binding globulins. What binds all steroids, but weaker than specific globulins?
    Albumin
  35. Which fraction (free or unfree) of the steroid hormone is biologically active?
    Free Form
  36. What is the purpose of the bound steroids?
    • Serve as a reservoir buffering against changes in production and clearance
    • Serve as means for transport of these highly hydrophobic substances
  37. What are the two primary means of steroid clearance?
    Hepatic and Renal
  38. What is the primary enzyme involved in steroid clearance?
    CYP3A4
  39. How are steroids metabolized in the liver?
    • Oxidation of steroid ring structure
    • Bile Salt formation
    • Excretion into intestine
  40. How are steroids metabolized by the kidney?
    • Glucouronidation and sulfation to increase solubility, decrease affinity for binding globulins
    • Removed in urine primarily
    • Inactive
  41. What are the five major defects associated with Steroidogenesis?
    • P450C21
    • P450C11
    • P450C17
    • P450ARO
    • 5-alpha Reductase
  42. What is the most common major defect in Steroidogenesis?
    P450C21
  43. This is an AR defect that presents in newborns. There is an inability to synthesize 11-deoxy-cortisol and 11-deoxy-corticosterone, which results in an inability to produce what two major steroid hormones? The result of this is that Progesterone and 17-alpha hydroxyprogesterone are diverted to androgen synthesis. This leads to masculinization of the female, as well as to salt wasting. What is the name of the disease, and what enzyme is defected?
    • Cortisol and Aldosterone
    • Congenital Adrenal Hyperplasia
    • P450C21
  44. In this defect in Steroidogenesis, there is an inability to produce cortisol and aldosterone. 11-deoxycortisol and 11-deoxycorticosterone are the major steroids produced in the adrenal gland. These are weak glucocorticoids and mineralocorticoids, but feedback is broken on regulation of their synthesis so they increase in concentration, giving them a greater effect. This can push toward hypertension. What is the defect involved?
    CP450C11
  45. In this AR defect in Steroidogenesis, there is an inability to produce 17-hydroxyprogesterone or 17-hydroxypregnenolone. Therefore, cannot make androgens OR cortisol. Can synthesize aldosterone and corticosterone though. Results in a cortisol deficiency and no androgens. What is the defect?
    P450C17
  46. In this defect in Steroidogenesis, there is an inability to synthesize steroids. What is it?
    P450ARO
  47. In this defect in Steroidogenesis, there is an inability to synthesize 5-alpha DHT. This results in a failure of testicular descent and masculinization of male genitalia.
    5-alpha Reductase
  48. What is the primary source for steroid formation?
    Cholesterol ester stores
  49. To be steroidogenic, a molecule must express what two things?
    • Side Chain Cleavage
    • Synthesize Steroids de Novo from Cholesterol
  50. What is the function of metabolism in steroidogenesis?
    • Regulates local steroid concentrations
    • Activates or inactivates steroids
  51. Steroid hormones mediate their cellular signaling via ligand activated transcription factors known as what?
    Nuclear Receptors
  52. The Nuclear Receptor Superfamily are members of what family of transcription factors?
    Zinc Finger Family
  53. What is the major function of the Nuclear Receptor Superfamily?
    Modulate transcription of target genes (increase or decrease transcription -- gene dependent)
  54. What modulates the transcription function of a receptor?
    Binding of Ligand
  55. Which domain of the nuclear receptor is highly variable and receptor specific, and associates with co-repressors or co-activators, thereby regulating transcription? Co-repressors and co-activators are ezymes that modify histone structure through acetylation or deacytlation.
    Amino Terminal Activation Factor (AF-1) Domain
  56. Which domain of the nuclear receptor is highly conserved, and has two zinc finger binding regions: has specific interaction with DNA recognition sequences (cis elements). There is a weak dimerization sequence: the nuclear receptors function as homo/heterodimers
    DNA Binding Domain (DBD)
  57. Which region of the nuclear receptor has a nuclear localization sequence? This signals transport of receptor to nucleus either upon synthesis or signals transport of the receptor to nucleus upon steroid hormone binding.
    Hinge Region
  58. Which domain within the nuclear receptor provides structure allowing each receptor to recognize and bind to its specific ligand with high affinity? This is a second strong dimerization domain. The Activating Factor (AF-2) domain within this domain binds co-activators or co-repressors and regulates transcription
    Ligand Binding Domain
  59. Which domain within the Ligand Binding Domain associates with co-repressors or co-activators after hormone induced conformational change?
    Activation Factor Domain II (AF-2)
  60. This nuclear receptor type is the classic steroid hormone receptor family (ER, AR, PR, GR, MR). Its ligands easily penetrate through the lipid bilayer. These receptors are located in the cytoplasm in the unliganded state. They are associated with heat shock proteins and other chaperone proteins to stabilize the receptor structure and keep it in the cytoplasm.
    Type I Nuclear Receptors
  61. What is the purpose of the heat shock and other chaperone proteins associated with the inactive (unliganded state) of Type I Nuclear Receptors?
    They stabilize the receptor structure and keep them in the cytoplasm
  62. With Type I Nuclear Receptors, what 4 things happen upon Ligand Binding?
    • Conformation Change
    • Chaperone Dissociates
    • NLS Exposed, Nuclear Translocation
    • DNA Binding to Target Genes
  63. These are DNA sequences that serve as binding sites for the nuclear receptor in the regulatory region (5'-flanking to the transcription start site) of the target gene.
    These are variations of a 'core' steroid response element and are typically gene specific
    They function as an 'inverted palindrome'
    Cis Elements
  64. Upon DNA binding, nuclear receptors recruit ___________, which increase the transcription rate of the target gene.
    Co-Activators
  65. What do Histone Acetyltransferases (HATs) do?
    Activate transcription
  66. What is the typical Histone Acetyltransferase (HAT) for nuclear receptors?
    SRC1, 2, 3
  67. HATs (typically SRC 1, 2, 3) _________ Arg/Lys residues in Histone 3 and 4. This reduces the ________ of the histone and thus the protein: DNA interaction between the nucleosome and DNA. This then facilitates ___________ formation (loose chromatin structure). There is then recruitment of _______ __________ ___. Transcription initiation and an increased rate of transcription occurs, which increases ________, and _______ _______. What is the final result?
    • Acetylates
    • Charge
    • Euchromatin
    • RNA Polymerase II
    • mRNA; Protein Levels
    • Altered Cellular Function
  68. Upon DNA binding, nuclear receptors recruit ____________, which decrease the transcription rate of target genes that are repressed by that hormone.
    Co-Repressors
  69. What are the major Co-Repressors?
    Histone Deacetylases (HDACs)
  70. Histone Deactylases (HDACs) _________ the Arg/Lys residues on Histone 3 and 4. This increases the ________ and thus increases protein: DNA interaction. This then condenses the chromatin structure, resulting in _____________ formation. _____ _________ ____ dissociates and cannot be recruited to target genes, resulting in decreased transcription. ________ and ________ levels decrease. What is the end result?
    • Deacetylate
    • Charge
    • Heterochromatin
    • RNA Polymerase II
    • mRNA & Protein
    • Altered Cellular Function
  71. This type of receptors have ligands that can easily penetrate through the lipid bilayer. They are located in the nucleus, and are DNA bound in the unliganded state. A conformational change results from ligand binding.
    Common types are retinoic acid receptors, vitamin D receptors, thyroid hormone receptors, and PPARs.
    Type II Nuclear Receptors
  72. Type I Nuclear Receptors are DNA-bound in the ________ state, whereas Type II Nuclear Receptors are DNA bound in the _________ state.
    • Liganded
    • Un-liganded
  73. In Type II Nuclear Receptors, the cis elements serve as an '________ _________' usually with a variable N spacer sequence of 0-5 nucleotides.
    Inverted Repeat
  74. The degree of transcriptional modification by a nuclear receptor is proportional to the __________ of that given hormone. What is this known as?
    • Concentration
    • Response Curve
  75. These are invaluable tools for treating endocrine diseases, such as cancer.
    • Antagonists
    • Agonists
    • Inverse Agonists
  76. This invaluable tool for preventing endocrine diseases blocks the ability of the receptor to bind ligand, and therefore the receptor remains in a pre-ligand binding state for that class. What is the tool, and what is an example of it?
    • Antagonist
    • ICI182780 (ER Antagonist): used to treat hormone sensitive breast cancers
  77. This invaluable tool for preventing endocrine diseases changes the conformation of the receptor such that the receptor switches from binding co-activators to co-repressors and actively suppresses target genes. What is the tool, and what is an example of it?
    • Inverse Agonist
    • Mifepristone (PR reverse antagonist)
  78. This invaluable tool for preventing endocrine diseases blocks the function of the receptor on some but not all target genes. It is cell type dependent. What is it, and what is an example of it?
    • Partial Agonist (aka Partial Antagonist)
    • Tamoxifen: ER receptor antagonist; in uterus is a weak agonist
  79. What are the two most common heat shock proteins and chaperone proteins associated with Type I Nuclear Receptors?
    • hsp 70, 90
    • Immunophilins
  80. In the Type I Nuclear Receptors what specifically dictates whether co-activators or co-repressors are recruited?
    DNA - Protein Interaction
  81. The Cis elements associated with the Type I Nuclear Receptors are palindromic, and are separated by what? They are not always perfectly palindromic, but can vary a little (70-80% conserved). What does the variations allow?
    • 3 NT Spacer (NNN)
    • Variations allow them to have specific action on the target genes (transcription vs repression)
  82. Within the Type II Nuclear Receptors, this is a member of the retinoic acid family, and can form a heterodimer partner with all type II receptors.
    Retinoid-X-Receptor
  83. In the Type II Nuclear Receptors, what dictates whether co-activators or co-repressors are recruited?
    Ligand Binding
  84. What are the 5 Type I receptor family members, and what specific ligand is associated with each?
    • Estrogen Receptor alpha & beta (ERalpha & ERbeta): Estradiol
    • Progesterone Receptor (PR): Progesterone
    • Glucocorticoid Receptor (GR): Cortisol (and synthetic glucocorticoids)
    • Mineralocorticoid Receptor (MR): Aldosterone
    • Androgen Receptor (AR): Testosterone & 5-alpha DHT
  85. What are the four Type II receptor family members, and what specific ligand is associated with each?
    • Vitamin D Receptor: Vitamin D
    • Thyroid Hormone Receptor (TRalpha & TRbeta): T3
    • Retinoic Acid Receptor (RAR, alpha, beta): Retinoic Acid
    • Peroxisome Proliferator Activated Receptor (PPARalpha, beta, gamma): Fatty Acids, Prostaglandins

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