Intracellular Hormone Receptors. Steroid versus Peptide Hormones Mechanism of Action of Steroid Receptors Cellular Localization and Structure of Steroid Receptors How Steroid Receptors Initiate Transcription Role of Hormone Response Elements (HREs)
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Steroid versus Peptide Hormones
Mechanism of Action of Steroid Receptors
Cellular Localization and Structure of Steroid Receptors
How Steroid Receptors Initiate Transcription
Role of Hormone Response Elements (HREs)
Interactions of Steroid Receptors with Other Pathways
Regulation of Steroid Receptors
Half-life in circulation short long
Speed of action fast slow
Duration of effect short long
Location of receptor membrane inside
Post-receptor regulation high low
Signal amplification high low
progesterone receptor (A and B)
estrogen receptor (alpha and beta)
thyroid hormone receptor
vitamin D receptor
retinoic acid receptor
- In the presence of hormone, they form R-H complexes in the nucleus and function as activators by binding to the same enhancers.
- Act as repressor or enhancer, depending on the physiological signals.
- thus, the response element serves as either enhancer or silencer.
Target geneResponses to hydrophobic hormones are mediated by intracellular receptors
Lipophilic hormone carried in blood
Hormone binds intracellular receptor inducing receptor dimerization and activation
Complex is imported into nucleus
Binds to “hormone response element” to regulate gene expression
“Hormone response element”
1. GR exists in an inactive form in the cytoplasm complexed with heat shock protein 90 (hsp90).
2. Glucocorticoid (G) diffuses across cell membrane and enters cytoplasm
3. G binds to GR changes conformation dissociates from hsp90
4. exposes a nuclear localization signal (stretch of aas) on GR.
5. G-GR (hormone-receptor complex, HR) enters nucleus, dimerizes with another HR.
7. Binding of HR dimer to enhancer activates transcription.
8. Most contain 2 zinc fingers (1) controls DNA binding, (2) controls dimerization
Critical residues for discriminating between GRE and ERE lie at the base of the first finger
-GRE = glucocorticoid responsive element /enhancer (sequence); ERE = estrogen
Specificity of DNA binding
-Hormone binding domains (HBD) in carboxyl terminus
-DNA-binding domain (DBD) 5’ to ligand binding domain
- Role of Heat Shock Proteins (HSPs)
- Role of Hormone Response Elements (HREs)
5’ flanking regionSteroid Receptor Action:Roles of Heat Shock Proteins and HREs
What is the mechanism of steroid receptor activation?
8-bromo cyclic AMP
+ PKA inhibitor
5’ flanking regionSteroid Receptors bind to Hormone Response Elements (HREs) on DNA
EXON 1…...Palindromic Sequences Allow Binding of Receptors as Dimers
5’ -AGAACAnnnTGTTCT- 3’
- Cell specific expression of receptors (don’t express both PR and GR in same cell. But sometimes they are in the same cell!)
- Other transcriptional regulation elements (cofactors)
- Formation of heterodimers versus homodimers (ie, thyroid hormone receptor with retinoic acid receptor)
How do we know it’s the HRE and DNA Binding Domain that interact to give specificity of transcriptional regulation? Here’s an experiment.
ERE bindingGRE bindingLigand
yes no estradiol
no yes cortisol
BOXHow does binding of Activated Steroid Receptor to HREs Enhance Transcription?
Protein Kinase C
Increased Expression of
collagenaseMolecular Mechanism through which Glucocorticoids inhibit Inflammatory Responses
C P D1 D1
RU486Activation of Progesterone Receptor by Dopamine in Absence of Progesterone
block translationUse of Antisense Oligonucleotides to Block Gene Expression
Block Gene Expression
C P D1 D1
oligo to PRBlockade of Dopamine Activation of PR by Antisense Oligonucleotides
phosphorylation of CREBEstrogen Phosphorylates CREB via the MAPK Pathway – Wade & Dorsa, 2003
- transcriptional: control of gene expression
- post-transcriptional: modulation of mRNA stability
- post-translational: rate of receptor degradation
-Estradiol decreases uterine ER expression
-Estradiol increases ER in pituitary, liver
-Estrogen up-regulates progesterone receptor in breast, uterus, hypothalamus
-Progesterone down-regulates estrogen receptor
-Androgen down-regulates estrogen receptor
First Midterm Exam