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GTS 351 > Cancer And Genetic Disease > Flashcards

Cancer And Genetic Disease Flashcards

1
Q

Two distinct gene groups are targets for cancer mutations.

A
  1. over expressed genes encoding proteins such a growth factors that promote cellular division.
  2. Suppressed genes encoding proteins that modify/ reduce cellular growth.
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2
Q

Define oncogene.

A

A gene of which the encoded protein can render a cell cancerous when over expressed or mutated.

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3
Q

How do proto-oncogene from another source become an oncogene inserted by a virus.

A

The virus integrates into the host genome next to the src gene (proto-oncogene) , the virus undergoes incorrect excision resulting in the src gene being included in the virus genome. When the genome is inserted into another cell the SRC will now be a oncogene.

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4
Q

What are pronto oncogenes

A

Are the normal and correctly regulated cellular version of the oncogenes.

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5
Q

Cancer have been shown to be due to:

A
  1. Over expression of proto-oncogenes.

2. Alteration by mutation within the cellular genome.

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6
Q

Model 1 on how viruses can elevate expression of oncogenes

A

Increased expression of the MHC proto-oncogene via promoter (LTR) insertion upstream of myc gene.

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7
Q

Model 2 on how viruses can elevate expression of oncogenes

A

Increased expression of the myc proto-oncogene via action of its enhancer. Viral enhancer located in LTR region.

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8
Q

How does translocation cause expression of oncogenes.

A

Placing a normal proto-oncogene under control of another strong cellular promoter or enhancer.

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9
Q

Example 1 of translocation elevate expression of oncogenes.

A
  1. Myc-gene and promoter is inserted in a head-to-head orientation downstream of the immunoglobulin enhancer.
  2. Immunoglobulin enhancer activates the myc-promoter, rather than its own promoter, resulting in elevated myc expression.
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10
Q

Example 2 of translocation elevate expression of oncogenes.

A
  1. Translocation yield a myc gene not close to any immunoglobulin regulatory elements.
  2. Removal of myc negative regulatory elements that normal repressed its expression occurred. In the absence of any repressors , myc expression is enhanced.
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11
Q

Jun-fos expression are normally produced in response to?

A

Growth-inducing factors

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12
Q

The abnormal synthesis of jun-fos will result in?

A

A cell which will be stimulated to grow continually and will not respond to growth- regulating signals.

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13
Q

What are the verbA oncogene.

A

A mutant of the thyroid hormone receptor.

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14
Q

V-ErbAalpha oncogene has a similar DNA bindings domain to c-ErbA but the hormone bindings domain has been mutated.

A
  1. It does no longer bind the hormone, but it still binds to gDNA. Thus no activation of transcription
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15
Q

How v-ErbA functions

A
  1. V-erba competes with c-Erb A for the same DNA binding site.
  2. It then inhibits and blocks the expression of genes that are normally induced and controlled by the thyroid hormone
  3. V-ErbA recruits a repressor (COR) resulting in the inhibition of transcription .
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16
Q

Mutation in the inhibitory domain of v-ErbA.

A

Abolish its ability to bind the co-repressor. It also abolish its ability to transform cells, even though it can still bind to DNA.

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17
Q

The relationship between v-Erb A and erythroblast.

A
  1. V-Erb A inhibits differentiation of erythroblast cells to nuclei-free erythrocytes by inhibiting the expression of a anion transporter protein.
  2. Combined introduction of v-erbB the erythroblasts replicate independent of external growth factors.
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18
Q

Facts about Tumour suppression genes

A
  1. These genes are normally involved in restraining cellular growth.
  2. Their inactivation will result in abnormal growth.
  3. In contrast to proto-oncogenes over expression or mutational activation of these anti-oncogenes does not result in cancer.
  4. The best know examples are the p53 gene and the retinoblastoma.
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19
Q

What is p53

A

A TF that is induced under condition of cellular damage, that activates genes responsible for inhibiting cellular growth during repair and also as an inhibitor of cyclin dependent kinases.

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20
Q

How does p53 affect gene expression?

A
  1. P53 stimulates the transcription of growth interfering genes (GIG) that inhibiting growth.
  2. Inhibit the expression of growth stimulating genes (GSG) whose protein products stimulating growth.
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21
Q

How does p53 suppress GSGs directly.

A
  1. Preventing an activator (A) to bind to its binding sites.
  2. Enhancing a tightly packed chromatin structure.
  3. Directly interacting with the activator preventing it to bind DNA.
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22
Q

P53 can repress expression of GSG indirectly.

A
  1. Stimulating the expression of an inhibitory protein such as p21.
23
Q

P21 function

A

P21 is a potent cyclin-dependent kinase inhibitor. The p21 protein binds to and inhibits the activity of numerous cyclins, and thus functions as a regulator of cell cycle progression at G1 and phase.

24
Q

The p53 activity can be negatively affected by:

A
  1. Deletion of the gene
  2. Inactivation of the gene by mutation
  3. Intact p53 is present but fail to be activated. Oncogenes such as MDM2 bind to p53 and mask its activity region.
25
Q

How does the MDM2 effect p53.

A

Binding of MDM2 to p53 protein induces ubi of p53.

MDM2 binding to ribosome proteins repress the translation of p53.

26
Q

What are some of the target genes of p53 TF.

A
  1. P21 ( 21 kDa)

2. BAX

27
Q

Function of BAX

A

The BAX protein functions to stimulate cell death under conditions of irreversible damage.

28
Q

Mechanism of action of p53.

A
  1. P53 is activated by damage to the DNA.
  2. P53 will stop cellular growth until the damage is repaired
  3. If the damage cannot be repaired p53 gets acetylated at lysine 120 which activates apoptosis via transcription of BAX.
  4. In the absence of p53 the damaged cell will continue to proliferate and if there are mutations in oncogenes, will form a cancer.
29
Q

What was the first anti-oncogene to be identified?

A

Retinoblastoma protein (Rb-1)

30
Q

What will happen if an organism is lacking Rb-1

A

The organism will not be viable thus Rb-1 is essential for normal development.

31
Q

Function of Rb-1

A

It acts through protein-protein interactions with transcription factor E2F. E2F stimulates several growth promoting genes, such as c-myc. Therefore Rb-1 acts as an anti oncogene by preventing the transcription of growth promoting gene.

32
Q

What happens if Rb1 undergoes modification or inactivation.

A

This will result in a lack of cellular control over the process of cell division. Cells grow uncontrolled causing cancer.

33
Q

Aside from binding to E2f and inhibiting its function what else does Rb1 bind to.

A
  1. I can also bind to histone deacetylase and histone methylated.
  2. Promotes the formation of a tightly packed chromatin structure.
34
Q

How is transcription regulated to promote growth genes using Rb and E2F.

A
  1. In normal cells Rb is phosphorylated and released from E2F so that transcription can happen .
  2. Rb is deleted or inactivated in cancer cells so that transcription can happen .
  3. In cancer cells Rb binds to oncogene and released from E2F so that transcription can happen.
35
Q

What proteins does Rb bind to ?

A
  1. Polymerase 1 transcription factor (UBF) = inhibits transcription by pol 1
  2. Transcription factor E2F = inhibits transcription by pol 2
  3. TFIIB = inhibits transcription by pol 3
36
Q

The relationship between p21 and Rb1

A
  1. P21 is activated by p53
  2. P21 is an inhibitor of the cyclin dependent kinases involved in Rb phosphorylation.
  3. P21 keeps Rb1 in it unphosphorylated form, inhibiting cellular growth.
37
Q

Regulation of microRNA expression.

A
  1. Some leukaemia: deletion of chromosome 13, and loss of miRNA genes results in cancer.
  2. In some ovarian cancers: miRNAs are down regulated due to being packaged in closed chromatin.
  3. Altered transcription of miRNA genes activated by p53 and repressed by c-myc.
38
Q

What components of the jun and fos dimer needs to be over expressed in cancer.

A

Both

39
Q

Mutations in transcription factor coding genes may result in?

A
  1. A functional transcription factor that binds to DNA but fail to activate gene expression
  2. Haploid insufficiency- the amount of protein made is not sufficient, due to only one copy of the gene being muted.
  3. Failure to respond to signals
40
Q

How does a mutation in the DNA sequence affect a transcription factor.

A
  1. Mutation in the DNA sequence coding for an transcription factor can cause that, that Transcription factor is not present in the cell. Thus there will be no transcription of the target gene of that transcription factor.
  2. A mutation in the target gene itself prevents the binding of the transcription factor.
41
Q

Mutations in transcriptional co-activators.

A
  1. If there is a mutation in both genes coding for the co-activator, thus resulting in no functional CBP is lethal.
  2. If there is a mutation in one gene coding for the co-activator, less co-activator present in the cell resulting in disease.
  3. Mutations in other genes can cause the incorrect protein to protein interactions removing a functional co-activator.
42
Q

Mutation in DNA methyltransferase enzyme can cause?

A
  1. Incorrect methylation that can cause under methylation ( genes that should closed are opened, over methylation ( genes that should be open are closed)
43
Q

Mutations in histone deacetylation and acetyltransferase enzyme can cause.

A
  1. Deacetylation mutation: chromatin that should be closed is now open
  2. Acetyltransferase enzyme: chromatin that should be open is now closed (Example: HAT activity )
44
Q

Class 1 mutation in RNA splicing (snRNA)

A

A gene mutation that affects mRNA splicing, thus there is a failure to produce the correct splice variant.

45
Q

Class 2 mutation in RNA splicing (snRNA)

A

Mutation renders an inactive splicing factor.

46
Q

An example of a mutation in alternative splice sites

A

If there is a mutation in one gene coding for the splice factor, the Tau protein will be 50% normal tau expressed and 50% alternative spliced tau. This imbalance can cause impact on its faction.

47
Q

Where in translation can mutation occur.

A
  1. Enzymes that process tRNA, mediate tRNA synthesis and tRNA binding of amino acids.
  2. Ribosomal proteins
  3. Translation initiation factors
  4. Regulators of translation ( eg. elF2B)
48
Q

How do you manipulate the activity of nuclear receptor family of transcription factors.

A
  1. Activity can be inhibited by a synthetic antagonist which competes with normal ligand for binding but that does not activate the receptor.
  2. The activity of the receptor can be stimulated using a synthetic ligand which binds to the receptor and activate it .
49
Q

Altering the activity of TFs in the inflammation pathway ( NFkB pathway) . I.e how to stop inflammation

A
  1. Enhanced expression of IkB
  2. Reduced. Expression of NFkB
  3. Inhibiting phosphorylation of IkB by aspirin
  4. Blocking the protein-protein interactions in the different proteins of the IkB kinase complex with a peptide.
50
Q

How does the drug that inhibits the interaction of p53 with MDM2.

A

The drug renders MDM2 inactive by blocking the binding site that p53 binds to, this allows p53 to be free in the cell to inhibit cancer growth.

51
Q

When you target histone deacetylase inhibitors ( chromatin will not be closed) what parts of the cell does this affect.

A
  1. Cell cycle: p21, cyclins
  2. Motility: alpha -tubulin
  3. Immunity an inflammation: NFkB, STAT3, TNF alpha
  4. Angiogenesis: HIF -1alpha, VEGF
  5. Metabolism: GLUT1
  6. Extrinsic apoptosis: death receptor, and death receptor ligands
  7. Intrinsic apoptosis: Bcl-2, bc1-X, BIM and BAM
52
Q

Designer zinc-finger

A
  1. It is possible to design zinc finger which will bind specifically to a DNA sequence in a target gene.
  2. Linking this finger to a transcriptional inhibitory domain can be used to switch off a target gene.
  3. Linking the finger to a transcription activation domain can switch on the target gene.
53
Q

Modulating RNA splicing in muscular dystrophy.

A
  1. In muscular dystrophy, exon 49 is deleted. This changes the reading frame producing a premature stop codon .
  2. An Antisense oligonucleotide (miRNA) to block the inclusion of exon 51
  3. This removes the stop codon and allows all downstream exon to translated.
  4. This produce a partially functional protein resulting in a less severe form of disease.
54
Q

How is the expression levels of any gene altered via miRNAs.

A
  1. synthetic dsRNA molecules that are complementary to the mRNA of a specific target RNA is made.
  2. These are transferred into cells.
  3. That are processed in the cytosol via dicer
  4. They then mediate blockage of translation as well as mRNA degradation.

GTS 351 (9 decks)

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