Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

[ONCG2004] Lung, Breast, And Prostate Cancer > 5: Gene Regulation By ARs And ERs > Flashcards

5: Gene Regulation By ARs And ERs Flashcards

1
Q

What distance do signals act for the below systems:
- autocrine
- paracrine
- endocrine

A
  • autocrine: affects cell producing them (eg GFs)
  • paracrine: diffuse short distance to affect nearby cells (eg neurotransmitters)
  • endocrine: acts on target sites far distance from site of synthesis (eg hormones)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are the 4 characteristics of a hormone?

A
  1. They are biochemical agents
  2. Synthesized and secreted by glands
  3. Circulate in the blood to other parts of the body
  4. Stimulate specific (target) tissues
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the 2types of hormones?

A

Lipid soluble and water soluble

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Compare water soluble to lipid soluble hormones

A
  • lipid soluble diffuse through plasma membrane, water soluble bind to receptors at surface of cell (cannot diffuse)
  • water soluble travel easily in blood, lipid soluble are transported by carrier proteins
  • lipid soluble alters expression of genes at nuclear level, water soluble results in series of intracellular events
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Where are the 9 areas that produce hormones in the body?

A
  • pineal
  • hypothalamus
  • pituitary
  • thyroid
  • parathyroid
  • adrenals
  • pancreas
  • testis
  • ovary
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Describe the difference in molecular structure between testosterone and estrogen

A

They differ only by a H3C group and double O bond in testosterone, single OH in estrogen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Describe the general molecular structure of a nuclear receptor

A

AF-1 (activating function 1) domain, located at N-terminus
DBD (DNA binding domain) = “zinc fingers”
LBD (ligand binding domain)
AF-2 domain, located at C-terminal
AFs help switch on transcription, and are important for coactivator interaction
Hinge region: provides flexibility between the DBD and LBD

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Fill in the blanks:
NRs activate transcription by preferentially binding to _____ _____ _____ of target genes.
Response elements act as _____ of receptor function.
Ligand binding induces _____ recruitment and ______ ______.

A
  1. Regulatory response elements
  2. Modulators
  3. Coactivator
  4. Transcriptional activation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are the 3 types of nuclear receptors?

A

Type I: ‘steroid’ receptors, generally homodimeric (AR, ERa, ERb, PR, GR)
Type II: repressions in absense of agonist, heterodimeric with RXR (retinoid X receptor) (TR, RAR, PPARy, RXR)
Type III: orphan nuclear receptors, heterodimeric with RXR (unknown ligands)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Describe the action of steroid (Type 1) nuclear receptors using androgen receptor as an example

A
  1. AR associated with HSP complexes in the cytoplasm to maintain inactive state
  2. Binding of testosterone or dihydrotestosterone (DHT) causes dissociation of HSPs, activating AR
  3. Homodimerization of activated ARs
  4. Translocation of homodimerised ARs to nucleus and bind to androgen response elements in DNA
  5. Recruitment of coactivators (eg p160, HMTs, p300/CBP, etc) to remodel chromatin via LxxLL motifs
  6. AR/CoAct complex recruits mediator complex, interacting with RNA polII ad TAFs
  7. Assembly of transcriptional machinery at promoter region initiates genes transcription
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is the role of p160 steroid receptor coactivators (SRC-1/2/3)

A
  • posses histone acetyltransferase (HAT) activity
  • acetylation of histones to relax chromatin structure, facilitating transcription
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What are some examples of histone methyl transferases and what do they do?

A

Eg: CARM1, PRMT
Methylae histones, contributing to chromatin remodeling

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What are p300 & CBP

A

Lysine acetyltransferases
Acetylate histone and non-histone proteins, enhancing transcriptional activity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are some examples of histone demethylases and what do they do

A

LSD1, JMJD2A
Remove methyl groups from histones, reversing repressive methyl marks and promoting gene activation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is the role of the LxxLL motif?

A

Contains leucine (L) residues separated by 2 unspecified amino acids (X).
Interacts with AF2 domain of nuclear receptors
Binds coactivators such as SRC-1/2/3, p300/CB etc
Coactivators possess HAT activity, which remodel chromatin, allowing transcription of DNA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Fill in the blanks:
Type II nuclear receptors, such as ____ ____ ____ (____s) form heterodimers with ____ ____ ____ (____s). They are located in the ____ even in the absence of their ligand.
In the absence of a ligand (such as ____-____ ____, ____) these receptors _____ transcription.

A
  1. Retinoic acid receptors (RARs)
  2. Retinoic X receptors (RXRs)
  3. Nucleus
  4. All-trans Retinoic acid (ATRA)
  5. Repress
17
Q

What do these stand for:
- HDACs
- KMTs
- KDMs

A

HDACs: histone deacetylases
KMTs: lysine methyltransferases
KDMs: lysine demethylases

18
Q

Describe the repressive action of unliganded type II nuclear receptors

A
  • RARs heterodimerise with RXRs in the absence of ligand (eg ATRA) in the nucleus
  • CoRepressors (eg SMRT/NCoR) remove acetyl groups from histones, condensing the chromatin
  • Repressive methyltransferase complexes add repressive epigenetic methyl marks to histones
  • ATP-dependent chromatin remodeling complexes remodel chromatin to a repressed state
  • all actions together result in transcriptional repression at Retinoic acid response elements (RAREs)
19
Q

What are the 2 types of ligands for type II nuclear receptors?

A
  • ATRA: all-trans-retinoic acid, RARa/b/y
  • 9-cis-RA, RXRa/b/y
20
Q

Describe the action of type II nuclear receptors

A
  • ligand binding (eg ATRA/9-cis-RA) relives repression of receptor
  • CoRepressors are displaced, and coactivators (eg SRC1/2/3, HMTs, HDMs, KATs) are recruited
  • coactivator complex recruits mediator complex, interacts with RNA polII and TATA-binding protein associate factors (TAFs)
  • initiates transcription at RAREs, resulting in gene activation
21
Q

T or F
- Helix 12 is re-orientated upon binding (eg of DHT/T/THG)
- H12 interacts with LxxLL motif of coactivators
- LBD facilitates DNA dimerisation

A
  • T
  • T
  • F, LBD facilitates RECEPTOR dimerisation
22
Q

Describe the function of the LBD in coregulator interactions

A
  • LBD involves 12a helix arrangement
  • facilitates receptor dimerisation
  • in a sense of agonist/ presence of antagonist, H12 interacts with CoRepressors complexes
  • agonist binding induces formation of H11, and realignment of H12, allows accessible surface to bind to coactivators
    (The side which is accessible changes which complexes interact: CoRepressors/coactivators)
  • H12 binds to LxxLL motif of coactivators
23
Q

What are DR3 and DR5 and how do they contribute to nuclear receptor specificity?

A

Direct repeat 3/5 base pair spacing.
There are 2 similar/indentical sequences (half-sites) separated by 3 or 5 base pars.
Nuclear receptors recognise and bind to these repeats
Eg for DR3: ERE, ARE, and GRE
For DR5: RARE

24
Q

What are the 2 roles of pioneer factors?

A
  1. Active role: actively ope chromatin to make it accessible for TFs and CoActs, enabling transcription
  2. Passive role: partially bound to inactive enhancers, maintaining a stat of readiness for rapid induction upon signal
25
Q

Fill in the blanks:
Nuclear receptors are guided to response elements by ____ ____.
ER is guided by ____ to its binding sites.
Active binding sites are marked by ____ ____, facilitating ER binding and _____ _____.

A
  1. Pioneer factors
  2. FoxA1
  3. Histone modifications
  4. Transcription activation
26
Q

Describe how FoxA1 facilitates the transcription of ER.

A
  • FoxA1 is a pioneer factor that guides ER to its binding sites
  • FoxA1 binds to forehead motifs and helps open up chromatin at the ERE.
  • Active binding sites are marked by histone modifications (H3K4me1, H3K4me2), facilitating ER binding and transcription activation
27
Q

What does type I (steroid) receptor agonist binding induce?

A
  • heat stress protein dissociation
  • nuclear translocation of steroid receptors
  • receptor dimerisation
  • rearrangement of H12 rendering CoAct binding surfaces accessible
  • recruitment of CoActs and transcriptional activation
28
Q

What does type II/III heterodimeric receptors agonist binding induce?

A
  • CoRepressors dissociation
  • CoAct recruitment
29
Q

Describe the structure of histones

A
  • small basic proteins
  • the core is composed of 2 copies of each H2A, H2B ad H3H4 tetramer
  • there are ~147 bps of DNA wrapped 1.7 times round the histone octamer
  • histone tails are positive, interacting with negatively charged phosphate backbone of DNA
30
Q

T or F
- transcriptional states are dependent upon genetic location, with Heterochromatic chromatin accessible to basal transcriptional machinery
- Heterochromatin composes telomeres, centromeres, and Barr body
- euchromatin has hypo-acetylated histones
- Heterochromatin is hyper-methylated

A
  • F: euchromatic chromatin is accessible to basal transcriptional machinery, not heterochromatic
  • T
  • F: euchromatin has hyper-acetylated histones (accumulation of acetylation makes it accessible)
  • T
31
Q

Describe Heterochromatin versus euchromatin

A

Heterochromatin:
- condensed DNA, transcriptionally silenced
- composes telomeres, centromeres, Barr body
- hypo-acetylated histones
- hyper-methylated histones

Euchromatin:
- accessible DNA, transcriptionally active
- hyper-acetylated histones
- hypo-methylated & hyper-phosphorylated

32
Q

Fill in the blanks:
Histone tails are highly ____ between species. They are subject to multiple, and sometimes mulatually exclusive, ____ ____, eg lysine acetylation.

A
  1. Conserved
  2. Covalent modifications
33
Q

List some examples of covalent modifications to histone tails

A
  • lysine:
    1. Acetylation
    2. Methylation (mono, di, tri-)
    3. Lactylation
    4. Crotonylation
    5. Acylation
  • arginine methylation
  • serine phosphorylation
  • threonine phosphorylation
  • glutamine serotonylation
34
Q

Fill in the blanks:
Lysine acetylation and arginine methylation lead to transcriptional _____, whereas some modifications are context dependent, such as lysine ____.

A
  1. Activation
  2. Methylation
35
Q

Describe how lysine acetylation causes transcription activation

A

Acetylation masks histone charges resulting in charge-charge repulsion between octamer and DNA backbone:

  1. Lysine is positive, when acetylated, the positive charge is removed.
  2. Acetylated H3/H4 decreases he overall positive charged associated with the histone octamer
  3. This decreases the electrostatic interaction between the histone complex and the negatively charged DNA backbone
  4. The DNA is more accessible to transcriptional machinery
36
Q

What is a KMT and list 4 examples

A

Lysine methyl transferase
Eg: MLL, EZH, G9a, SET

37
Q

What enzymes facilitate:
1. lysine to mono-methyl lysine
2. di-methyl lysine to mono-methyl lysine
3. lysine to acetyl lysine
4. acetyl lysine to lysine

A
  1. Methyl added, KMT (lysine methyl-transferase)
  2. Methyl removed, KDM (lysine de-methylase)
  3. Acetyl added, KAT (lysine acetyl transferase)
  4. Acetyl removed, HDAC (histone deacetylase)
38
Q

What are some examples of pharmaceutical:
1. Anti-androgens (for prostate cancer)
2. Selective estrogen receptor modulators (for breast cancer)

A
  1. Flutamide, Bicalutamide, Enzalutamide
  2. Tamoxifen, Raloxifene, Toremifene, Lasofoxifene

[ONCG2004] Lung, Breast, And Prostate Cancer (8 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions