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Flashcards in Lipophilic Deck (20):
1

lipophilic hormones use what kind of receptors?

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

2

classic steroid nuclear receptors

include classic steroidal hormones like

mineralcorticoids, glucocorticoids, estrogen, progesterone, and adrogens

3

orphan nuclear receptor

retinoids, thyroid hormones, vitamin D, xenobiotics, androstane

4

where are nuclear receptors located? what do they do?

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

5

molecular structure of NRs

3 domains

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

6

AF1

activation function 1 domain

independent of ligand binding

can alter conformation of entire receptor

7

DBD

DNA binding domain

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

8

LBD

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

9

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

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

10

active NR has what co-proteins attached to it

the ligand binding domain is attached to a co-activator

11

Primary (early) response to steroid hormones

steroid--receptor cause synthesis of primary response proteins

then primary response protein shuts off gene

12

Secondary (delayed) response to steroid hormones

primary response proteins activate secondary response genes

13

Estrogen receptors

two major types

ERalpha and ERbeta

estrogen dependent, both activate separate genes on two different chromosomes

14

ER alpha

expressed most abundantly in reproductive tract

ovaries, uterus, vagina

mammary gland, hypothalamus, endothelial cells, vascular smooth muscle

15

ER beta

expressed abundantly in ovaries, prostate,

less abundantly in lungs, brain, bone, vasculature

16

which ER is expressed in breast cancer?

both alpha and beta

beta considered the predominate form

17

Signal--Receptor complex

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


18

big take away points of Genomic effect of ERs

ER located in nucleus

Estrogen binding causes dimerization and translocation into the nucleus

19

Tamoxifen

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

20

Non-genomic ER signaling

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

effects mediated through metabolic changes as well as gene expression