nuclear hormone receptors

Question 1

describe the general structure of nuclear receptors

Answer 1

1. N terminal
2. activation function 1: modulatory
3. dna binding domain. (consists of two zinc fingers that bind specific parts of DNA sequences)
4. hinge region for flexibility
5. ligand binding domain (binding of ligand activates or represses gene transcription. induces dimerization to allow leading to translocation into nucleus)
6. activating function 2: modulatory (interacts with co-activators or repressors)

Question 2

what do zinc fingers in the DBD consist of

Answer 2

P box which determines sequence specificity of receptor dna binding
D box for dimerization
zinc ion anchors receptor in specific location

Question 3

what are the hormone response elements like for steroid and non steroid hormone receptors in DNA

Answer 3

steroid:
6-3-6 after 3 bases inverted palindrome of first 6
non steroid:
6-n-6 n is anywhere between 1-5

co activators required for gene transcription

Question 4

what is the effect of Liver and retinoid x receptors in the absence of ligands on DNA and transcription.

Answer 4

corepressor proteins recruited
which interact with histone deactylases
deacetylation of lysines allows histones near hormone response element to be more compact, DNA tightly coiled
actively repressed transcription on target genes

Question 5

what is the effect of Liver and retinoid x receptors in the presence of ligands on DNA and transcription.

Answer 5

co activator proteins recruited
histone lysine acetylation via histone acetyltransferases
acetylation allows histones near hormone response element to be capped. DNA unwinds.
actively enhanced transcription on target genes

Question 6

what are the class 1 steroid hormone receptors and their characteristics

Answer 6

estrogen receptor alpha
estrogen receptor beta
androgen receptor
progesterone receptor
glucocorticoid receptor
mineralocorticoid receptor

needs ligands to promote gene treanscription
bound to chaperone proteins in cytoplasm
homo dimerized

Question 7

describe the action of steroid hormones

Answer 7

the hydrophobic steroid hormone diffused across cell membrane
steroid hormone displaces the chaperone protein in cytoplasm
a homodimer is formed which crosses the nucleus membrane
the steroid hormone receptor dimer binds to the steroid response element upstream of the target gene.
this inhibits or initiates gene transcription

Question 8

what are GR therapeutic uses

Answer 8

agonists used for asthma, topical anti-inflammatories, IBD, immunosuppression
ex: hydrocortisone, dexamethasone, prednisolone

Question 9

what are MR therapeutic uses

Answer 9

agonists for adrenocortical insufficiency: fludrocortisone
antagonists for oedema: eplerenone

Question 10

what are PR therapeutic uses

Answer 10

agonist oral contraceptive ex: norethisterone
antagonist emergency birth control ex: ulipristal and mifepristone

Question 11

what are ER therapeutic uses

Answer 11

agonists hormone replacement therapy ex: estradiol
antagonists for breast cancer ex: tamoxifen (selective estrogen receptor modulator, antagonist in breast, agonist in bone (reduces osteoporosis maintains calcium levels.) inactive in uterus (increased risk of uterine cancer). could be due to co activator distribution or estrogen receptor subtypes)

Question 12

what are AR (androgen) therapeutic uses

Answer 12

agonists for anemia, osteoporosis, weight gain ex: oxymetholone, testosterone
antagonists: prostate cancer ex: flutamide

Question 13

what are SERDS

Answer 13

selective estrogen receptor degraders used in ER+ breast cancers. increases proteolysis of ER. decreased levels of receptor. more effective than SERMS)
ex: fluvestrant

Question 14

what are characteristics of class 2 non steroid hormone receptors

Answer 14

includes thyroid hormone receptor, retinoic acid receptor, retinoid x receptors, ppar, vitamin D receptor (VDR).

ligand dependent and independent transcription
bound to co repressors in nucleus
homo and hetero dimers

Question 15

describe non steroid nuclear hormone action

Answer 15

uptake of hydrophobic agonists by transporter proteins
movement of ligand to nucleus via binding proteins like FABP CRABP
binding proteins offload ligands into receptor hetero/homodimers formed
co repressor on heterodimers displaced by co activators
interactions with DNA and transcription factors lead to inhibition or initiation of gene transcription

Question 16

what are some theraputic uses of non steroid nuclear hormone receptors

Answer 16

RAR and RXR agonists for psoriasis and acne tretinoin and acitretin
VDR agonists for rickets ex: cholecalciferol
TR agonists for underactive thyroid ex: t4 and t3
PPARgamma agonists for diabetes: pioglitazone

Question 17

what do PPAR alpha agonists do

Answer 17

fibrates (e.g., bezafibrate) are used in treatment of hyperlipidemias. increase lipid metabolizing enzymes. decrease LDL cholesterol increase HDL cholesterol.

Question 18

what do PPAR gamma agonists do

Answer 18

ex: pioglitazone
used in DM2 treatment. recovers insulin sensitivity. regulates adipocyte differentiation. more adipocytes produced with better insulin sensitivity.

Question 19

what are peroxisomes

Answer 19

small, membrane-enclosed organelles that contain enzymes.

Question 20

what do PPAR regulate the transcription of

Answer 20

the peroxisome proliferator activates receptors regulate transcription of
lipoprotein lipase (hydrolyses triglycerides)
HMG CoA synthetase (initiates ketogenesis)
CYP450A6 (fatty acid oxidation in microsomes)
Acyl CoA oxidase (fatty acid oxidation in peroxisomes)