Steroid Hormone/Nuclear Receptors Don DeFranco, Ph.D., dod1@pitt.edu - PowerPoint PPT Presentation

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Steroid Hormone/Nuclear Receptors Don DeFranco, Ph.D., dod1@pitt.edu

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Title: Steroid Hormone/Nuclear Receptors Don DeFranco, Ph.D., dod1@pitt.edu


1
Steroid Hormone/Nuclear ReceptorsDon DeFranco,
Ph.D., dod1_at_pitt.edu
  • Steroid Hormone Structure
  • Nuclear Receptors
  • Description
  • Structure
  • Signal Transduction
  • DNA-Binding Properties
  • Regulation of Gene Expression
  • Diseases
  • Drug Targets

2
Steroid Hormone/Nuclear ReceptorsClinical
Relevance
  • Endocrine Disorders (Hormone Insensitivity
    Syndromes Cancer)
  • Regulators of Various Metabolic Processes
  • Therapeutic Use to Reduce Inflammatory Diseases

3
GLUCOCORTICOIDS
  • Reduce inflammation and immune responses
  • In clinical practice since 1948
  • 10,000,000,000./year market size in US

4
Glucocorticoids Side Effects
5
Steroid Hormones Derived from Cholesterol
Lipid Soluble Able to cross plasma membrane by
passive diffusion
6
  • SUMMARY OF INITIAL STEPS IN STEROID HORMONE
    SIGNAL TRANSDUCTION
  • Stimulation of hormone production by releasing
    hormones or factors that are synthesized and
    secreted from neuroendocrine cells (e.g.
    Adrenocorticotrophic hormone ACTH from
    specialized cells in the anterior pituitary
    stimulates glucocorticoid production from
    specialized adrenal cortical cells).
  • Transport of hormone to its target cell via
    plasma transport proteins in the bloodstream.
  • Dissociation from the plasma transporter proteins
    and diffusion of the free hormone across the
    plasma cell membrane.
  • Hormone encounters receptor either in the
    cytoplasm or the nucleus.

7
Hypothalamic-Pituitary-Adrenal (HPA) Axis
Regulation of Cortisol Synthesis and Secretion
8
Nuclear Localization of Steroid Receptors
Unliganded GR
Liganded GR
Unliganded/ Liganded ER
NOTE Steroid Receptors Shuttle Between the
Nucleus Cytoplasm
9
Domain Organization of Steroid Receptors
10
Steroid Hormone Receptors Limited Forms
Hormone Receptor (s) Androgens AR Min
eralocorticoids MR Estrogens ERa ER
b Progesterone PRA PRB Glucocort
icoids GR GRb
11
TWO RECEPTORS FOR ESTROGEN ER? ER?
Note Both types of ER can form homodimers (e.g.
ER?/ER?) or heterodimers (i.e. ER?/ER?)
12
Estrogen Receptor Distribution Within the Body
13
Differential Actions of ERa and ERb
14
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15
Ligands for Some Nuclear Receptors
Vitamin D
16
Ligands for Various Orphan Receptors
17
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18
  • Active ingredient of Gugulipid
  • Gum resin of Commiphor mukl
  • In use since 600 BC
  • Antagonist of FXR
  • (Farnesoid or Bile Acid Receptor)
  • Lowers cholesterol and triglyceride
  • levels

19
  • Active ingredient in St. Johns Wart
  • Extract of Hypericum perforatum
  • In use over 2000 years
  • Ligand for PXR
  • (Pregnane X or Xenobiotic Receptor)
  • Induction of CYP3A4

20
NR Classification
  • Nuclear receptors can be classified by
  • Their DNA binding specificity
  • Their hormone binding specificity
  • Their dimerization properties

21
DNA Binding Configurations of NRs
HETERODIMER
MONOMER
HOMODIMER
  • Steroid hormone receptors bind primarily as
    homodimers
  • Retinoid X Receptor (RXR 9-cis RA) is a common
    dimerization partner for various nuclear
    receptors including thyroid hormone receptor,
    retinoic acid receptor (all-trans RA), vitamin D
    receptor and others

22
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23
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24
Glucocorticoid Response Unit of the PEPCK Gene
GR
GR
HNF3
HNF4
COUP
1
CEBP/ß
TBP
-27
-90
-325
-380
-410
-445
Accessory DNA-binding Factors Required!! (Can
impart tissue-specificity)
NOTE Phosphoenolpyruvate carboxykinase (PEPCK)
gene is glucocorticoid regulated in liver only
25
Estrogen Regulated Promoters Association of other
Transcription Factors
All EREs on chromosomes 21 22
From Myles Brown laboratory (Dana Farber Cancer
Institute), 2005, 2006
Genome wide analysis
26
Basic Mechanisms of Transcriptional
Activation/Repression by the Glucocorticoid
Receptor
27
Glucocorticoid Side Effects Molecular Mechanisms
28
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)
29
Histone Acetylation/Deacetylation
30
Other transcription factors
NOTE Rubinstein-Taybi Syndrome caused by
mutations in CBP.
NOTE Overexpression of some coactivators (e.g.
Amplified in Breast Cancer-1 AIB-1) associated
with hormone-independent breast cancer
(From Glass and Rosenfeld)
31
Other transcription factors
NOTE HDAC inhibitors in clinical trials for
cancer treatment
(From Glass and Rosenfeld)
32
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33
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?
34
Thiazolidinediones (TZD) PPAR-? Ligands
Activation of PPAR-? in fat cells increases fatty
acid and triglyceride uptake and storage as well
as impacts adipokine gene expression (e.g.
downregulates the insulin resistance factor
resistin while upregulating the insulin
sensitizing factor adiponectin)
Endogenous PPAR-? ligand
35
Steroid Hormone Action
Steroid Hormone Action
Selective Estrogen Receptor Modulators (SERMs)
36
Estrogen Receptor Ligand-binding Domain
Ligand-induced Conformational Change
Helix 12 Contacts Coactivator proteins!
37
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38
MECHANISM OF SERM ACTION
SERM as Agonist Recruitment of Coactivators! (e.g.
Tamoxifen in uterus)
SERM as Antagonist Recruitment of Corepressors!
(e.g. Tamoxifen in breast)
39
  • Summary or Nuclear Receptor Action SPECIFICITY
    DETERMINANTS
  • Hormone binding
  • DNA binding
  • Cooperation with DNA-bound accessory factors
    (tissue-specificity)
  • Recruitment of coactivator and/or corepressor
    complexes (i.e. histone modifications-alterations
    in chromatin structure)
  • Ligand-induced conformational changes
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