Term
| Steroid hormones are structurally related, despite representing a diversity of physiological functions. What some examples of this? |
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Definition
1) Gonads- testosterone, estrogen, progesterone
2) Corticosteroids- glucocorticoids (cortisol) regulate gluconeogenesis and play a role in immunosuppression and inflammation.
3) Mineralocorticoids- aldosterone regulates water and salt uptake in the andrenal gland. |
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Term
| Why do steroids require transport proteins synthesized in the liver to reach their targets? |
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Definition
Steroid hormones are hydrophobic and have low water solubility in blood!
Remember STD
Hormone production is STIMULATED by neuroendocrine secretions, they are TRANSPORTED to target cells via transport proteins and they DISSOCIATE from these proteins and diffuse across the plasma membrane of their target cells. |
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Term
| Describe the important structural features of steroid hormone receptors (i.e. what domains do they have)? |
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Definition
1) DNA-binding components
2) C-terminal steroid-binding domains
3) N-terminus exhibits sequence diversity
4) Can exist in cytoplasm and migrate to nucleus, or originate in nucleus
** Act independently in and in heterologous contexts**
Remember, specific steroid hormone receptor sub-types may exert distinct physiological effects (there are two receptors for estrogen from different genes). |
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Term
True: False
Nuclear receptors are members of a larger superfamily of proteins with common domain organization and AA homology, particularly in the DNA-binding domain. Receptors for many small lipid-solube hormones, vitamins and metabolites localize to the nucleus |
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Definition
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Term
| How do nuclear and steroid receptors relate to "hormone response elements" (HRE)? |
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Definition
1) 2 Zinc-finger motifs (4 cysteine residues) of these receptors bind DNA in these closely related DNA sequences (12-15 nucleotides).
** HREs are "consensus" sequences and need not be exact **
2) Steroid receptors generally bind as homodimers, while many non-steroid nuclear receptors bind HREs as heterodimers with obligate RXR partner receptors. |
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Term
| How can nuclear receptors regulate transcription? |
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Definition
1) NRs bound to HRE can enhance RNA Poli II activity from linked promotor
2) Concentrate with other DNA-bound transcription factors to make "hormone response units" (HRU). HRU associations can determine cell-type specificity of hormone response.
3) |
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Term
| How is liver-specific glucocorticoid induction of PEPCK achieved? How does it relate to "hormone response units"? |
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Definition
Hepatocyte-specific nuclear factors bind within glucocorticoid response units (GRUs) of PEPCK gene.
The GRU is the HRU, PEPCK is the gene target and the nuclear factors are accessory- DNA-binding factors. |
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Term
| How is transcriptional repression achieved by Glucocorticoid Receptors (GRs)? |
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Definition
1. NRs recruited to target genes not through DNA-binding, but through alternate t-factors.
2. Anti-inflammatory and immunosuppressive function arises from GR interaction with t-factor such as NF-kB, that are active in this response. GR represses transcription of their genes. |
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Term
| True:False Transcriptional activation and repression by Nuclear Receptors always requires DNA-binding |
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Definition
False!
Remember, glucocorticoid receptor-mediated repression of inflammation acts through its binding to t-factors that are active in those processes. |
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Term
1) How do Coactivator proteins act to activate transcription?
2) How do they relate to Rubinstein-Taybi Syndrome (short with mental retardation, risk of b-cancer and leukemia with death in early childhood)? |
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Definition
1) Large, multisubunit complexes that link DNA-bound NRs to transcriptional machinery
Can contain specific enzyme activities (Histone acetyltransferase) or recruit such enzymes to chromatin to regulate gene expression.
2) Mutation in CBP coactivator leads to Histone Acetyltransferase deficit. |
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Term
| How do "corepressor" proteins regulate transcription? |
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Definition
1. Unliganded, DNA-bound nuclear receptors often recruit Histone Deacetylase enzyme that tightens chromatin and inhibits gene expression (HDAC is co-repressor).
2. Liganded-DNA-bound NRs can also recruit co-repressors (pro-inflammatory cytokines recruited by glucocorticoid receptor) |
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Term
| What have HDAC inhibitors been used for clinically? |
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Definition
| Limit tumor growth in cancer cells |
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Term
| What are glucocorticoids most commonly used for in clinical settings. How are they naturally regulated in the body? |
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Definition
-Anti-inflammatory and immunosuppressive actions
- Secreted specifically from adrenal cortex with diurnal rhythm (peak at 8am and trough at 4pm) and stress-induced responsiveness. |
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Term
| How to glucocorticoids (GCs) relate to mineralocorticoid receptors (MRs)? |
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Definition
GCs bind GCRs and MRs with equal affinity.
In tissues where MRs and GCRs are both expressed, cells protect themselves from MR effects by 11B-HSD-2, which converts active cortisol to cortisone.
11B-HSD-1 carries out the reverse action (expressed in skin and bone, for example). |
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Term
| How do Peroxisome Proliferator-Activated Receptor-gamma (PPAR-y) and members of the PPAR subfamily act? What are there ligands? |
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Definition
Primary- master regulator of adipocyte differentiation and function.
Secondary- Regulate peroxisome proliferation
Ligands include prostaglandins, arachidonic acid and oxidized linoleic acid. |
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Term
| What are thiazolidinediones (TZDs)? |
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Definition
synthetic ligans for PPAR-y such as rosiglitazone.
Have been somewhat effective in treating type II diabetes and adipose tissue update by skeletal muscle, but taken of f market largely because of CV risks and weight gain.
(Ligands that prevent Cdk5 phosphorylation of PPAR-y may be better) |
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Term
| Why is Peroxisome Proliferator-Activated Receptor-delta (PPAR-d) of clinical interest? |
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Definition
Like PPAR-y, PPAR-d is bound by FAs and eicosinoids, and regulates lipid and glucose metabolism.
In mice, PPAR-d ligands has been shown to protect again athlerosclerosis |
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Term
| What are selective estrogen receptor modulators (SERMs)? |
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Definition
Its a nuclear receptor modulator.
Increases estrogen effects in target tissues such as bone and CV system, but limit harmful effects such as enchanced risk of break cancer |
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Term
| Why is endocrine ablation via nuclear receptor modulators sometimes dangerous? |
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Definition
| Secondary tissue effects (often through partial agonist activity of some antagonists) |
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