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L2 Stem Cells > Oncogenes > Flashcards

Oncogenes Flashcards

1
Q

How was Rous Sarcoma Virus (RSV) discovered? (5)

A
  • Sarcoma removed from the breast of a chicken, ground up and filtered
  • Filtrate injected into another chicken
  • Chicken develops sarcoma
  • Concluded only a virus would be small enough to pass through the filter
  • Thought that cancer was an infectious disease
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2
Q

What happens when you infect cells with RSV in vitro? (2)

A
  • Cells form foci
  • Cells show similar metabolism to those isolated from tumours
    (RSV transforms cells in vitro)
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3
Q

What is cell transformation?

A

Conversion of a normal cell into a cancer cell

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4
Q

What are foci?

A

Clusters of tumour cells

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5
Q

What are the 2 possible explanations for the transformed RSV cells passed on their phenotype to other cells?

A
  • RSV particle transforms the progenitor cells and then transforms their offspring so the virus must be present to maintain the transformed phenotype
  • RSV particle transforms the progenitor cells which somehow transmit the phenotype to their offspring in the absence of the virus
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6
Q

How was it discovered how RSV cells pass on their phenotype? (5)

A
  • Made a temperature sensitive RSV mutant where the viral proteins are functional at 37 degrees but not 41
  • Infected cells at 37 degrees, saw the transformation
  • Raised the temperature to 41 degrees, transformation was lost
  • Reverting back to 37 degrees restored the transformation
  • Concluded that the presence of the virus is required to maintain the transformed phenotype
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7
Q

What are the properties of transformed (cancer) cells? (9)

A
  • Altered morphology
  • Loss of contact inhibition
  • Anchorage independent growth
  • Ability to proliferate indefinitely (immortalisation)
  • Can grow without growth factors
  • High saturation density
  • Inability to halt proliferation in the absence of growth factors
  • Increased uptake of glucose
  • Tumorigenicity
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8
Q

What are the viral constituents of RSV? (4)

A
  • Gag
  • Pol
  • Env
  • Src
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9
Q

Which RSV genes are required for viral replication? (3)

A
  • Gag
  • Pol
  • Env
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10
Q

Which RSV gene is required for transformation?

A

Src

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11
Q

What is the difference between c-src and v-src? (3)

A
  • Src is present in the genome of normal organisms in the c-src form
  • C-src is a proto-oncogene
  • V-src is an oncogene
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12
Q

What is an oncogene?

A

A gene capable of transforming a normal cell into a cancer cell

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13
Q

What is a proto-oncogene?

A

A precursor of an active oncogene

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14
Q

What causes cancer? (2)

A
  • Cancer is induced by mutagens which mutate growth-controlling genes
  • If mutagens mutate proto-oncogenes they induce the formation of tumours
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15
Q

What is segment recombination? (2)

A
  • Cut up segments of the proto-oncogene and the oncogene
  • Recombine using enzymes to identify which bit of the proto-oncogene changes to induce cancer
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16
Q

What mutation occurs in Ras to make it oncogenic? (2)

A
  • G12V
  • G12C
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17
Q

What are examples of proto-oncogenes? (2)

A
  • Ras
  • Myc
18
Q

How does wildtype Ras work? (4)

A
  • Inactive Ras bound to GDP
  • GEF causes Ras to dissociate from GDP and bind to GTP
  • Ras is active when bound to GTP and activates downstream targets
  • GAP causes GTP hydrolysis so Ras is bound to GDP and inactivated again
19
Q

What kind of molecule is Ras?

A

Small GTPase

20
Q

What impact does a G12V/G12C mutation have on Ras signalling

A

Ras is unable to hydrolyse GTP to GDP so remains active and can’t be switched off, even in the absence of growth factors

21
Q

What are the 3 ras genes in the human genome?

A
  • H-ras
  • K-ras
  • N-ras
22
Q

Which mutated form of ras is the most frequent driver of tumour development? (2)

A
  • K-ras
  • KRAS G12C mutation is the most prevalent in lung cancers
23
Q

What is AMG510? (3)

A
  • New drug AMG510 is a specific inhibitor for G12C mutated K-ras
  • AMG510 binds to KRAS G12C in the GDP-bound form and prevents binding to GTP so it can’t be activated
  • No effect on wildtype Ras
24
Q

What are the results from AMG510 testing? (3)

A
  • AMG510 inhibits tumour growth in mice
  • Efficiency improves in combination with chemotherapy/MEK inhibitor
  • AMG510 is not effective on mice lacking an immune system
25
Q

What is MEK?

A

Downstream target of Ras

26
Q

What happens when you combine AMG510 with anti-PD1 (immunotherapy)?

A

AMG510 potentiates immunotherapy

27
Q

How does AMG510 potentiate immunotherapy? (3)

A
  • AMG510 boosts the expression of pro-inflammatory cytokines
  • Increases infiltration of tumours by T-cells and dendritic cells
  • The T-cell response is long term, reintroducing KRAS G12C cancer cells after being cured had no effect
28
Q

What is the problem that arises with KRAS inhibition therapy?

A

Rapid adaptive resistance

29
Q

What are the mechanisms of adaptive resistance to KRAS inhibition? (5)

A
  • Mutations to the drug binding site on the KRAS so the inhibitor can’t bind
  • Mutations in the other KRAS allele which compensates for the inhibition of the original mutant KRAS
  • Amplification of KRAS which decreases the efficacy of the inhibitor
  • Additional G12 mutations
  • Mutations in effectors downstream of KRAS
30
Q

What are the 3 members of the myc family?

A
  • c-myc
  • N-myc
  • L-myc
31
Q

What kind of molecule are the myc proteins?

A

Growth-promoting transcription factors

32
Q

What are the 3 mechanisms by which the myc oncogene can arise?

A
  • Gene amplification
  • Chromosomal translocation
  • Pro-virus integration
33
Q

Where is N-myc amplification seen?

A

In 30% of childhood neuroblastoma cases

34
Q

How does gene amplification of myc cause cancer?

A

More copies of the gene results in too much myc protein being made causing uncontrolled growth

35
Q

How does chromosomal translocation make myc oncogenic? (2)

A
  • In Burkitt lymphoma, myc gene is translocated onto a different chromosome which puts it under the control of an immunoglobulin promoter in lymphoid cells
  • Causes excessive production of myc protein and uncontrolled proliferation of lymphoid cells
36
Q

Where is chromosomal translocation of myc seen?

A

Burkitt lymphoma

37
Q

How does pro-virus integration of myc cause cancer? (2)

A
  • Avian Leukosis Virus (ALV) can insert into the genome, transcriptional promoter
  • If AVL inserts upstream of myc, causes increased expression and high levels of myc protein = uncontrolled growth
38
Q

How do growth factor receptor mutations cause cancer?

A

Truncated versions of epidermal growth factor (EGF) receptor can be constitutively active in the absence of growth factors

39
Q

How is the Ras proto-oncogene activated?

A

Point mutation (G12 substitution) causing a constitutively active protein

40
Q

How is the Myc proto-oncogene activated?

A

Gene amplification/chromosomal translocation/insertional mutagenesis causing overexpression of normal myc protein

41
Q

How is the EGFR proto-oncogene activated?

A

Structural changes causing constitutive activation

L2 Stem Cells (12 decks)

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