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Cancer Biology > Ch. 7: Tumor Suppressor Genes > Flashcards

Ch. 7: Tumor Suppressor Genes Flashcards

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1
Q

Do oncogenes act dominantly or recessively?

A

dominantly

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2
Q

What function do proto-oncogenes normally have in a cell?

A

proliferation, protein synthesis, and survival

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3
Q

What types of mutations convert proto-oncogenes to oncogenes?

A
  • changes to gene expression
  • changes to protein sequence
  • increase protein activity
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4
Q

What function do tumor suppressor genes normally promote in a cell?

A

inhibition of cell growth, promote apoptosis

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5
Q

What types of mutations in
proto-oncogenes convert them to oncogenes?

A

Loss of fxn mutations: decreased expression, decreased function
at the protein level

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6
Q

Are tumor suppressor genes dominant or recessive fashion?

A

recessive

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7
Q

What is a tumor suppressor gene?

A

a gene whose inactivation leads to increased likelihood of cancer development

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8
Q

Are cancer-causing genes dominant or recessive? (experiment)

A

1970s-1980s
- conducted cell fusion and injected it into an animal
* Results:
* Most cells from tumors that were caused by
viruses – dominant
* Most cells from tumors that were not caused
by viruses – recessive

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9
Q

What was one of the first studied tumor suppressor genes?

A

retinoblastoma

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10
Q

What is retinoblastoma?

A

rare childhood eye tumor

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11
Q

What are the two types of retinoblastoma?

A
  • sporadic
  • familial
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12
Q

Sporadic retinoblastoma

A

mild version (tumor in 1
eye, no cancer recurrence after tumor removal)

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13
Q

Familial retinoblastoma

A

aggressive version, parent
had RB, (tumors multiple sites of both eyes, still change of cancer recurrence in eyes and other tissues after tumor removal)

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14
Q

What is thought to give rise to retinoblastomas?

A

precursor cells that give rise to rods/cones are thought to give rise to retinoblastomas

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15
Q

Individuals with familial RB have increased risk of…

A

other tumors and giving to their children

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16
Q

Bilateral

A

increased risk of tumors in other areas

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17
Q

Genetics of Familial RB

A
  • 1 mutant allele arose in germline (all cells in organism have this)
  • 2nd mutant allele arose early development/ childhood in precursor
    RB cells à poised to proliferate
  • Once the mutation is in the germ lineage (egg or sperm), it can be given to offspring
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18
Q

genetics of sporadic RB

A
  • Both mutant alleles occurred in somatic cells, in precursor RB cells, during early development/ childhood. Separately.
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19
Q

Will individuals with sporadic RB have increased chance of passing this on to their offspring?

A

No, because the mutant RB allele is not created in early development when all of their cells are created and it is localized in eye cells (so eggs/sperm are not affected)

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20
Q

RB types can also be classified as ____

A

hits

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21
Q

“Hit”

A

refers to a somatic mutation

22
Q

How many hits are needed for familial and sporadic RB transformation?

A
  • familial: only need 1 additional hit for transformation
  • sporadic: need 2 hits (more rare)
23
Q

What are the types of alteration that can affect tumor suppressor genes?

A
  1. regular mutation rate
  2. loss of heterozygosity
  3. promoter methylation
24
Q

Alteration- regular mutation rate

A

changes to nucleotides based on errors in DNA replication or exposure to mutagens

25
Q

Alteration- loss of heterozygosity

A

a genetic event when one of two alleles at a heterozygous locus is lost.

26
Q

Alteration- promoter methylation

A

methylation of cytosines in the promoter region of a gene that subsequently causes the inhibition of
transcription

27
Q

Are mutation rates common or rare?

A

rare
* 10 -6 per cell generation
* Likely will get first mutation in some cells based on regular mutation
(Rb-/Rb+)
* Not likely to get a second mutation in the same gene in the same cell
via regular mutation
* Second hit -> mechanism not dependent on mutation rate (Rb-/Rb-)

28
Q

What is loss of heterozygosity?

A
  • a genetic event when 1 or 2 alleles at a heterozygous locus is lost
  • proved to be the case for some RBs
29
Q

Mechanisms that contribute to loss of heterozygosity

A
  • Mitotic recombination
  • Gene conversion
  • Chromosomal non-disjunction
30
Q

What is promoter methylation?

A

The cell methylates DNA to control gene expression
- methyl groups are added to Cs
- Generally, lots of DNA methylation in a promoter region, tends to inhibit transcription of a gene

31
Q

Promoter methylation of some TSGs progressively
increases with _______

A

cancer progression

32
Q

Hypermethylated promoter of p16 is associated with
____________________

A

pre-cancerous tissues

33
Q

Promoter methylation of some TSGs may be…

A

an early step in cancer progression

note:?
1) Chance for early detection
2) Target for cancer prevention

34
Q

Tumor suppressor genes

A
  • promote cancer when inactivated
  • prevent cancer when active
35
Q

What is one common familial cancer syndrome (like Rb)?

A

Neurofibromatosis

36
Q

What is neurofibromatosis?

A

benign tumors, neurofibromas in sheaths surround nerves
- can occasionally become malignant
- common mutation in NF1 tumor suppressor gene

37
Q

Peripheral nervous system

A

nerves that branch from the
brain and spinal cord; make
connection between central
nervous system and body
parts

38
Q

myelin sheath

A

made of proteins and
phospholipids, insulates nerve cells, increases speed of electrical impulses

39
Q

Schwann cells

A

helps form myelin sheaths

40
Q

What kind of growth are neurofibromas?

A

complex growths
- contain multiple different cell types

41
Q

What is NF1?

A

Neurofibromin- GTPase activating protein (GAP)
- catalyzes the hydrolysis of GTP to GDP + P
- it puts RAS in its inactive state

42
Q

T/F Loss of NF1 function has the same result on the cell as hyper-activation of RAS.

A

True

43
Q

How does loss of NF1 contribute to neurofibromas? (experiment) (lecture 7 part 2, slide 14+)

A
  • Scientists use mouse models to understand function of cancer related genes
  • Strategy: Gene knockout. Delete 1 or more copy of the gene and see the effects on the animal.
  • Step 1: Use homologous recombination to replace
    gene of interest (NF1) with neomycin resistance gene
  • Step 2: Introduce stem cells with knockout allele into
    a blastocyst (early mouse embryo).
  • Step 3: Transplant early mouse embryos into a
    surrogate mom mouse, she has chimeric babies
  • Step 4: Breed the chimeric progeny with one another
  • Step 5: Use the NF1 +/- (heterozygous) mice for experiments
  • Results: NF1 homozygous mutant embryos are not
    viable
44
Q

So, how can you determine the result of loss of both NF1 copies in an adult mouse?

A

Some creative genetics
- conditional gene knockouts (Cre-ER system)

45
Q

Steps of Cre-ER system

A
  • Step 1: Use homologous recombination to add LoxP
    sites to gene of interest (NF1)
  • Step 2: Introduce stem cells with floxed allele into a
    blastocyst (early mouse embryo).
  • Step 3: Transplant early mouse embryos into a
    surrogate mom mouse, she has chimeric babies
  • Step 4: Breed the chimeric progeny with one another
  • Step 5: Keep breeding in such a way that you end up
    with homozygous NF1 Fl/Fl and TSP-Cre
46
Q

You suspect gene X is involved in thyroid cancer. You breed mice to try to make a homozygous knockout mouse but find it is an essential gene. What is an experiment you can do to test the effect of gene X in adult mice?
* A) Make a mouse with the following genotype: GeneX Fl/Fl + Thyroid-CreER)
and add tamoxifen during development.
* B) Make a mouse with the following genotype: GeneX Fl/Fl + Thyroid-CreER)
and add tamoxifen during adulthood.
* C) Make a mouse with the following genotype: GeneX Fl/Fl + Myeloid-CreER)
and add tamoxifen during development.
* D) Make a mouse with the following genotype: GeneX Fl/Fl + Myeloid-CreER)
and add tamoxifen during adulthood

A

B

47
Q

How does loss of NF1 contribute to neurofibromas?

A
  • Loss of NF1 in Schwann cells can only cause neurofibromas when
    mast cells are heterozygous for NF1 KO allele
  • Role for paracrine signals. NF1 -/- Schwann cells secrete growth factors
    which act on nearby NF1 -/+ mast cells. Get complex neurofibromas which
    include various cell types.
48
Q

Other RAS-GAP’s (like NF1) act as ______________ in other cancers

A

tumor suppressor genes

49
Q

APC is a tumor suppressor gene that contribute to
____________

A

colon cancers

50
Q

APC

A
  • Follows the same genetic
    pattern as Rb
  • Involved in WNT signaling
    pathway
  • Loss of APC causes stabilization of B-catenin, which can enter the nucleus and cause transcription of target genes
  • -> constitutive activation of WNT signaling pathway
  • -> subsequent activation of
    oncogene leads to cancer
51
Q

KEAP1 is a tumor suppressor gene
in _________

A

lung and other cancers

52
Q

KEAP1

A
  • In normal conditions, KEAP1 allows an E3 ubiquitin (Ub) ligase to add Ub to
    NRF2, and NRF2 is degraded by the proteasome
  • In stressful conditions, KEAP1 ROS or carcinogens bind to KEAP1 and release NRF2, NRF2 can then
    accumulate and enter the nucleus and cause the txn of antioxidant genes
  • In cancers, loss of KEAP1, causes constitutive activation of detox genes

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