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Foundations To Medicine 2 > Examples Of Gene Regulation > Flashcards

Examples Of Gene Regulation Flashcards

1
Q

Whaat happens if an activator binds to an enhancer sequence?

A

It stabilizes the basal transcription apparatus (RNA pol, and the general transcription factors), and transcription levels increase

Many 1000s of bp May separate enhancer region and core promoter

Bind of activator to the enhancer increases efficiency of RNA pol. Transcription initiation

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2
Q

What are the 3 general ways transcription factors may act as repressors ?

A
  1. Competition
  2. Quenching
  3. Blocking
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3
Q

How May repressors perform competition?

A

May compete for enhancer sequence: activator vs repressor proteins to bind to the enhancer region which may reduce transcription levels

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4
Q

How May repressor proteins perform quenching?

A

Occurs when a repressor protein binds to abs interferes with the DNA-binding domain KD an activator protein

This reduces transcription levels.

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5
Q

How do repressor proteins perform blocking?

A

Occurs when the repressor protein binds to the activation domain of an activator protein and prevents it from interacting with the basal transcriptional machinery

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6
Q

Which species express the hypoxia inducible factor (HIF-1)?

A

Most, if not all, oxygen breathing species

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7
Q

Explain the hypoxia response

A
  • Hypoxia is a reduction in the normal level of tissue oxygen tension, and it occurs during several patho physiological processes including tumor genesis
  • HIF-1 activity leads to the Upregulation of genes that are involved in many aspects of cell survival, glucose metabolism, angiogenesis, cancer progression, and invasion
  • Requires a coordinate response where many genes are switched on or switched off to cope with this challenge
  • HIF-alpha and HIF-Beta transcription factors must dimerize, then bind to a specific DNA sequence called hypoxia response element (HRE) 5’ -TACGTG-3’
  • HRE is found upstream on many different genes to regulate their concerted
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8
Q

What does HIF do?

A

Regulates gene expression

HIF- alpha inducible oxygen sensitive

HIF-beta (ARNT)-constitutive

Both of the above form two branches of attachment domain

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9
Q

Discuss prolyl hydroxylase relaxation to HIF-1

A

High oxygen - HIF-1alpha is hydroxylated by prolyl hydroxylase & quickly degraded by the proteosome

Low/no oxygen- HIF-1alpha stabilized, moves to the nucleus & dimerizes with HIF-1B to activate multiple genes that enhance oxygen delivery to tissues and/or energy supply via glycolysis

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10
Q

How does a hypoxia state(HIF-1) ?

A

Under pathologically low oxygen levels (hypoxia state), HIF-alpha isn’t degraded and will translocate into the cell nucleus

In the nucleus, HIF-alpha will hetero-dimerises with HIF-1B

The final HIF-1alphabeta dimer is able to bind the hypoxia-response element (HRE) Sequence which is found upstream of many genes which are required for the survival 9f cells during hypoxia

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11
Q

Explain HIF- 1 as a therapeutic target

A
  • Anemia
  • Inflammation
  • Cancer

Stroke, solid cancer tumors, etc

Solid cancers are quick growing and hungry- they are often hypoxic - learning how to inhibit HIF-1alphs/HIF-1beta mediated gene expression may provide a way of selectively killing tumors

Hence the interest in hypoxia

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12
Q

What are glucocorticoids?

A

These are a major class of steroids

  • Steroids are small hydrophobic molecules
  • Involved in modulation of a large number of metabolic, cardiovascular, immune and behavioral functions
  • Intracellular effects are mediated by the glucocorticoid receptor
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13
Q

Describe the glucocorticoid receptor

A

The glucocorticoid receptor is a zinc finger type TF

  • The activated GR complex up-regulates the expression of anti-inflammatory genes in the nucleus and represses the expression of pro-inflammatory proteins in the cytosol
  • Various synthetic glucocorticoids are available; used either as replacement therapy in glucocorticoid deficiency or to suppresses the immune system
  • a key anti-inflammatory treatment
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14
Q

Describe the hormone response element (Cis element)

A

DNA sequence of the glucocorticoid response element:

5’ AGAACAnnnTGTTCT3’
3’TCTTGT nnn. ACAAGA5’

THE “n” represents any nucleotide
-note the inverted repeats

These Hormone Response Elements. (HREs) are DNA sequences found in the promoter and regulatory sequences of many genes

-Another example of how COORDINATED GENE REGULATION at manysites across the genome is accomplished in the eukaryotic cell

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15
Q

In the absence kf glucocorticoid (cortisol)…

A

The GR is held in the cytoplasm as part of an inactive multi-protein complex

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16
Q

What happens when cortisol binds to the GR ?

A
  • When glucocorticoids binds to GR, it dissociates from regulatory complex
  • the GR forms a dimer
  • moves in to the nucleus
  • Binds to the hormone response element (HRE)
  • Induces expression of target genes
17
Q

Glucocorticoid receptor requires…

A

Coactivatir proteins to interact with the basal transcription machinery

18
Q

How can glucocorticoid receptor dimer interact with repressor?

A

They interact with repressors which inhibit interaction with the basal transcription machinery

19
Q

What is the Myc/max system?

A

A regulatory mechanism for switching between gene activation or repression

Myc has a transcriptional regulation domain, but it may not bind to DNA unless it dimerizes

Myc regulates expression of many genes involved in cell cycle progression

20
Q

What happens in the absence of Myc?

A

Max forms a homodimer & it represses gene transcription

In non-proliferating cells

  • Max expressed
  • Myc not expressed

Tran#cription of many genes important fir the cell cycle (proliferation) is inhibited

21
Q

What happens in the presence of Myc?

A

Myc/Max Herero dimers is formed to activate gene expression

22
Q

Explain Myc/Max regulation 9f gene expression by control of dimerization

A

Gene activation occurs when both Myc and Max are made in th3 cell at the same time

  • Max prefers Myc as a partner
  • Max will always heterodimerize with Myc, if possible

Gene Reppression results when only the Max protein is made in the cell
-Homodimers of Max will form if Myc is not available

23
Q

Explain MYC overexpression

A

Occurs in tumors

  • MYC overexpression dramatically disrupts the equilibrium between activation and repression of genes
    • Estimated that cMYC regulates about 15% of all genes
  • Myc overexpression favors Myc/Max complexes
    • Impairs differentiation and promotes cell proliferation
    • A STEP IN THE PROGRESSION OF CANCER
24
Q

Explain differential expression of hemoglobins

A

Human hemoglobin A(HBA) is just one member of structurally/functionally related proteins

Fetal hemoglobin (HbF): tetramer f two a-chains and two y-chains
  -Expression if these chains begin at conception with y-chain expression exponentially decreasing soon after birth

Hemoglobin A: tetramer if two a-chAins and two B-chains
-Expression of B begins at conception with exponential increase to plateau at 6 month

Hemoblobin A2( HbA2): tetramer of two a-chaain# and two delta chains
 -expression of delta chain is expressed at low levels at birth
25
Q

Summar8ze differential expression in hemoglobin

A

A) developmental changes in globin expression
-the percentage of total globin chains are plotted against age from time of conception

B) organization of the globin gene families-2 chromosomes
-locus control regions found 1000s of bp upstream of the globin genes on both chromosomes

-These Cis regulatory elements strictly coordinate the expression of the globin genes

What 8s the copy number of the alpha gene in a human?

4 each person has 2 copies of chromosome 16

26
Q

What 8s the transcription code factor for gene regulation?

A

The combination of transcription factors expressed by a cell define a cell

27
Q

Where are the hem9glob8n genes located fir HbA?

A

Alpha gene family on chromosome 16

B-globin located on chromosome 11
The two copies of the alpha gene on chromosome 16 are designated a1 and a2. Each can provide a-gl9bin chains that combine with B-globin chains

28
Q

What are the two forms of naturally interfering RNAs?

A

Micro RNA(miRNA)

siRNA- short interfering

29
Q

Describe when each globin chain fluctuates

A

Y-chain- peaks and plateaus from 6 months before birth to birth where it decreases

Alpha-chain - peaks in 6 months before birth that plateaus permanently

B-chain gradually rises at birth and peaks at 6 months after birth

30
Q

Who won a Nobel prize for RNA interference (RNAi)?

A
  • In2006, Andrew Fire and Craig C. Mello shared the Nobel Prize in physiology or medicine for their work on RNA interference in the nematode worm C. elegans, which they published in 1998
  • “Arguably the most important advance in biology in decades”
31
Q

What are functions of miRNA?

A
  • derived from specific ds-pre-miRNA species
  • regulates expression by repressing by representing mRNA translation
  • Mostly endogenous (from genome )
  • artificial microRNAs are used in the laboratory to study gene function
32
Q

What are the characterized by siRNA?

A
  • derived from long dsRNA and ‘random’ processing
  • regulates expression by mRNA degradation
  • often exogenous (from outside the cell, I.e. virus or injected)

*additional small interfering RNAs have been identified recently having various functions

33
Q

Describe the function of miRNA processing

A
  • Long Pri-miRNAs are processed to pre miRNAs hairpin structures (about 70 nt) by Drosha
  • Pre-miRNA transported to cytoplasm by Exportin-5
  • Dicer further processes them to single stranded RNA and initiates the formation of the RNA-induced silencing complex (RISC)
  • RISC binds imperfectly to the 3’ untranslated region of TARGET mRNA
  • Inhibition of the ribosome ability to translate protein from mRNA transcript
34
Q

Describe the functioning of siRNA

A
  • DICER also processes long dsRNA into siRNA (small interfering RNA)
  • siRNA has perfect complementarity with the 3’ untranslated region of target mRNA
  • Perfect complementarity leads to endonuclease activity and target mRNA is cleaved, no protein is translated from the destroyed mRNA
35
Q

Summarize mechanism of translational regulation by miRNA

A

MicroRNAs regulate gene expression by binding to sequence elements in the 3’ UTR of a specific mRNA and imperfecta base pairing with it
-This prevents interaction of the translationary machinery with the 5’ cap structure

This is an example of gene regulation by preventing a mRNA from getting translated miRNA RISC complex base pairs imperfectly with target RNA

36
Q

Explain the mechanism of degradation of mRNA by siRNA

A

Short interfering RNAs regulate gene expression by perfectly binding to sequence elements in the 3’ UTR of a specific mRNA and base pairing with it.
-Perfect pairing siRNA with mRNA within the RISC complex will activate RISC endonuclease AGO2 activity & mRNA will be cleaved and not translated

This is an example if gene regulation by destroying mRNA transcript

siRNA- RISC complex base pairs perfectly with target RNA

37
Q

Summarize miRNA and cancer correlation

A

An example of a RNA which can be processed by drosha and Dicer to produce multiple mature miRNAs (sequence areas of miRNA shown in red)

  • Some miRNAs are normally involved in regulation of cell proliferation
  • The genes that encode these miRNA are amplified (DNA sequence is duplicated) in tumors cells
  • These cancerous cells then lose cell growth regulation and the cancer gets larger

Foundations To Medicine 2 (37 decks)

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