Lipophilic

Question 1

lipophilic hormones use what kind of receptors?

Answer 1

nuclear receptors, which includes classic steroid nuclear receptors and orphan receptors

Question 2

classic steroid nuclear receptors

Answer 2

include classic steroidal hormones like

mineralcorticoids, glucocorticoids, estrogen, progesterone, and adrogens

Question 3

orphan nuclear receptor

Answer 3

retinoids, thyroid hormones, vitamin D, xenobiotics, androstane

Question 4

where are nuclear receptors located? what do they do?

Answer 4

in the cytosol or nucleus

after signal binding they either translocate to nucleus and begin transcription or they’re already in the nucleus and bind to signal and then begin transcription

Question 5

molecular structure of NRs

Answer 5

3 domains

a) activation function 1 domain
b) DNA binding domain
3) ligand binding domain

Question 6

AF1

Answer 6

activation function 1 domain

independent of ligand binding

can alter conformation of entire receptor

Question 7

DBD

Answer 7

DNA binding domain

highly reserved, binds to DNA sequences called “hormone response elements” upstream of target gene

Question 8

LBD

Answer 8

ligand binding domain

binds to various molecules, agonist or antagonist which regulates ligand dependent activation of receptor

upon ligand binding, the AFT2 region of the LBD undergoes conformational change, which recruits coactivators and cosuppressors

Question 9

the inactive NR receptor has what co-protein attached to it?

Answer 9

co-suppressor: inhibitory protein attached to the ligand binding domain

Question 10

active NR has what co-proteins attached to it

Answer 10

the ligand binding domain is attached to a co-activator

Question 11

Primary (early) response to steroid hormones

Answer 11

steroid–receptor cause synthesis of primary response proteins

then primary response protein shuts off gene

Question 12

Secondary (delayed) response to steroid hormones

Answer 12

primary response proteins activate secondary response genes

Question 13

Estrogen receptors

Answer 13

two major types

ERalpha and ERbeta

estrogen dependent, both activate separate genes on two different chromosomes

Question 14

ER alpha

Answer 14

expressed most abundantly in reproductive tract

ovaries, uterus, vagina

mammary gland, hypothalamus, endothelial cells, vascular smooth muscle

Question 15

ER beta

Answer 15

expressed abundantly in ovaries, prostate,

less abundantly in lungs, brain, bone, vasculature

Question 16

which ER is expressed in breast cancer?

Answer 16

both alpha and beta

beta considered the predominate form

Question 17

Signal–Receptor complex

Answer 17

dimerization–>conformational change–>binding to “estrogen response sequence” in DNA –> ER-DNA complex recruitment of co-activators that modify chromatin as well as steroid receptor co activator SRC-1

SRC has histone acetyltransferase activity (HAT).

chromatin remodeling allows other cofactors to bind, leading to DNA synthesis via the GENERAL TRANSCRIPTION APPARATUS

Question 18

big take away points of Genomic effect of ERs

Answer 18

ER located in nucleus

Estrogen binding causes dimerization and translocation into the nucleus

Question 19

Tamoxifen

Answer 19

ER antagonist, bind and change conformation to produce susceptibility to co-repressor binding: nuclear hormone receptor co-repressor are recruited to complex (NcoR)

NcoR further recruits proteins such as histone deacetylase I (HDAC1) that act on histone proteins to stabilize nucleosome structure, prevents interaction with GTA

Question 20

Non-genomic ER signaling

Answer 20

some ERs located in plasma membrane, some are GCPRs and TRK types

effects mediated through metabolic changes as well as gene expression