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STEROID HORMONE/NUCLEAR RECEPTORS

STEROID HORMONE/NUCLEAR RECEPTORS. Krystle A. Frahm, PhD University of Pittsburgh Department of Pharmacology & Chemical Biology Division of Endocrinology & Metabolism Pittsburgh Institute for Neurodegenerative Diseases Center for Neuroscience. Progesterone receptor A, B (PRA, PRB).

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STEROID HORMONE/NUCLEAR RECEPTORS

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  1. STEROID HORMONE/NUCLEAR RECEPTORS Krystle A. Frahm, PhD University of Pittsburgh Department of Pharmacology & Chemical Biology Division of Endocrinology & Metabolism Pittsburgh Institute for Neurodegenerative Diseases Center for Neuroscience

  2. Progesterone receptor A, B (PRA, PRB) Androgen receptor (AR) Glucocorticoid receptor (GR) Estrogen receptor α, β (ERα, ERβ) Mineralocorticoid receptor (MR) Steroid Biosynthesis Derived from cholesterol

  3. Glucocorticoids: Therapeutic Uses Endocrine Disorders: -acute or chronic adrenal insufficiency -congenital adrenal hyperplasia Non-endocrine Disorders: -rheumatoid arthritis -bronchial asthma -inflammatory bowel disease -inflammatory dermatosis -organ transplantation -allergic diseases -occular diseases

  4. Glucocorticoids: Side Effects

  5. Nuclear Localization of Steroid Receptors Unliganded GR Liganded GR NOTE: Steroid Receptors Shuttle Between the Nucleus & Cytoplasm

  6. Classical and Non-Classical NR Signaling

  7. Steroid Hormone Receptors: Limited Forms Hormone Receptor(s) Androgen AR Mineralocorticoids MR Estrogens ERa ERb Progesterone PRA PRB Glucocorticoids GR GRb

  8. TWO RECEPTORS FOR ESTROGEN ER & ER AF-1 DBD LBD AF-2 ER-a ER- 23% 86% 24% 58% 12% Homology: Note: Both types of ER can form homodimers (e.g. ER/ER) or heterodimers (i.e. ER/ER)

  9. Estrogen Receptor Distribution Within the Body ER ER, ER

  10. Dominant Roles for Select ER Subtypes ERa ERß • Apoptosis in prostate cancer cells • Enhancement of glucose stimulated insulin secretion (pancreatic ß cells) • Folliculogenesis • Reduced intestinal inflammation (reduced colon carcinoma risk) • Stimulation of uterine growth • Bone metabolism • Mammary gland development • Negative feedback in hypothalamus

  11. EMERGING RESEARCH SELECTIVE ER ISOFORM AGONISTS

  12. Erbeta distribution in the male and female mouse hypothalamus

  13. ER alpha and ER beta in the Hypothalamus

  14. NONSTEROIDAL ER ACTIVATORS Phytoestrogens (from soy) • Contain flavinoids (e.g. Genistein), which are weakly estrogenic Schaefer O, et al., (2003) 8-Prenyl naringenin is a potent ERalpha selective phytoestrogen present in hops and beer. J Steroid Biochem Mol Biol Vol. 84: pp 359-360.

  15. NONSTEROIDAL ER ACTIVATORS Xenoestrogens or Environmental Estrogens • Industrial chemicals or their byproducts with estrogenic activity • Effects on human health are controversial but recent studies suggest that long term exposure (i.e. BPA) may increase risk of obesity and breast cancer in women Bisphenol (BPA) Polychlorobiphenyls (PCBs)

  16. Glucocorticoid Response Unit of the PEPCK Gene GR GR HNF3 HNF4 COUP +1 CEBP/ß TBP -27 -90 -380 -445 -410 -325 Accessory DNA-binding Factors Required!! (Can impart tissue-specificity) NOTE: Phosphoenolpyruvate carboxykinase (PEPCK) gene is glucocorticoid regulated in liver only

  17. DNA-Induced Conformational Changes in Glucocorticoid Receptor: Impact on Gene Regulatory Properties Transcriptional Activation Transcriptional Repression GR + Other Transcription Factors GR GR Direct DNA Binding Tethering

  18. CHROMATIN: Higher Order DNA Compaction Within the Nucleus Histone Core: 2 copies each of H2A, H2B, H3, H4 (all basic proteins-rich in Arg, Lys residues)

  19. Histone Acetylation/Deacetylation

  20. Other transcription factors NOTE: HDAC inhibitors in clinical trials for cancer treatment (From Glass and Rosenfeld)

  21. Nuclear Receptors as Drug Targets • Reproductive or Endocrine Disorders • Hormone-dependent Cancers (ER-breast cancer, AR- prostate cancer) • Metabolic Diseases (PPAR- for Type 2 Diabetes and Metabolic Syndrome) NOTE: Ligands for nuclear receptors are small ligands that are cell permeable CELL OR TISSUE-SPECIFIC LIGANDS POSSIBLE?

  22. Estrogen Receptors in Breast Cancer Estrogen receptor negative Estrogen receptor positive

  23. Estrogen receptor ligands elicit different tissue-specific responses raloxifene 4-hydroxytamoxifen Z-pseudo ( Z-OHT ) diethylstilbestrol estradiol N N O O O H O H O H O Estrogen target tissues H O H O S H O H O Breast agonist agonist antagonist antagonist Uterus agonist partial agonist antagonist partial agonist Bone agonist agonist agonist partial agonist partial agonist agonist ???? agonist Liver CNS agonist antagonist antagonist agonist Steroid Hormone Action Steroid Hormone Action Selective Estrogen Receptor Modulators (SERMs)

  24. THERAPEUTIC ANDROGEN PREPARATIONS Anabolic Steroids • Tetrahydrogestrinone (THG) • Metabolized quickly and had been difficult to detect since it degrades during standard gas chromatography and mass spectrometry procedures • Toxicity profile unknown

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