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Cancer Biology > CBIO2: Oncogenes and tumour suppressors > Flashcards

CBIO2: Oncogenes and tumour suppressors Flashcards

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1
Q

How do cancer cells become cancerous?

A
  1. Activation of oncogenes

2. Inactivation of tumour genes

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2
Q

Define Proto-oncogene

A

a normal gene which, when mutated, becomes an oncogene

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3
Q

Oncogene

A

a gene that codes for a protein that potentially promotes oncogenesis when overexpressed, activated or mutated

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4
Q

Oncovirus

A

a virus that can cause cancer

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5
Q

Retrovirus

A

RNA viruses that produce dsDNA copies of their genome that integrate into the host chromosomes

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6
Q

What do tumour suppressor genes do?

A

Normal genes that slow down cell division, repair DNA mistakes and promote apoptosis.

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7
Q

How do tumour suppressors work?

A

They inhibit components that transduce signals from growth factors to prevent uncontrolled division

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8
Q

How many copies of a tumour suppressor do you need?

A

Only 1 copy of the gene needs to be present to prevent tumour formation, if both copies are mutated and inactive – they can cause cancer

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9
Q

What is an APC gene?

A

If there are mutations in this suppressor (Adenomatous Polyposis Coli gene), then there’s an increased the risk of colon cancer in individuals with familial adenomatous polyposis

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10
Q

How do the majority of mutations come about?

A

They are acquired (spontaneous)

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11
Q

More than half of all cancer cases display what mutation?

A

Acquired TP53 gene mutations.

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12
Q

What are the two broad specifications of tumour suppressors?

A

Gatekeeper

Caretaker

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13
Q

How does a tumour suppressor act as a gatekeeper?

A

Negatively regulate cell growth by encoding proteins which inhibit proliferation, induce apoptosis, inhibit angiogenesis or induce cell adhesion. An example is RB1 which encodes Retinoblastoma protein.

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14
Q

How does a tumour suppressor act as a caretaker?

A

Maintain chromosomal integrity and prevent cell division if DNA is damaged. An example is TP53 which also possesses gatekeeper properties.

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15
Q

What is Retinoblastoma?

A

A rare type of cancer that mostly affects children in one or both of their eyes. Retinal cells grow rapidly and stop during a baby’s early development, but uncontrolled growth leads to this disease.

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16
Q

How does Retinoblastoma come about?

A

40% of cases occur due to a mutation in the RB1 gene (first tumour-suppressor gene to be cloned) and affects both eyes. However, in 60% of cases, there is no mutated gene and it is unknown how they arise.

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17
Q

How does RB suppress tumours?

A

It binds to transcription factor E2F in order to inactivate it as it keeps the cells at the checkpoint between G1 and S.

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18
Q

What has to happen to RB to allow the cell to proceed to S-phase?

A

RB must be hyperphosphorylated to inactivate it.

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19
Q

What can mutated RB not do?

A

Bind to E2F therefore it cannot prevent damaged cells from proceeding to S phase

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20
Q

How many copies of RB do you need to maintain cell function?

A

One functional copy of RB1 can produce sufficient RB to protect the cell

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21
Q

What is the two-hit Knudson hypothesis?

A

Inherited cancers occur when one defective gene copy is inherited and the other copy acquires a mutation

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22
Q

Tumour suppressor genes behave like _________.

How?

A

Recessive alleles

- Heterozygotes display the wild-type phenotype

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23
Q

When do tumour suppressor genes not act like recessive alleles?

A

When the mutations can behave in a dominant manner such as predisposition to retinoblastoma. This is because a person with one mutated allele is at a greater risk of developing retinoblastoma as one mutation can be acquired to cause the disease.

24
Q

Name a tumour suppressor gene that is expressed in almost all cells of the body

A

p53, Its function is altered in the majority of cancers

25
Q

How are mutations acquired?

A 
loss of nucleotides
UV or ionising radiation
oncogene signalling
hypoxia 
inhibition of transcription
26
Q

What do individuals with Li Fraumeni syndrome have?

A

Most TP53 mutations are acquired but individuals with Li Fraumeni syndrome have inherited a TP53 mutation and will develop a cancer by the age of 30

27
Q

List the downstream effects of p53

A
  • Cell cycle arrest
  • DNA repair
  • Bloackage of angiogenesis
  • Apoptosis
28
Q

How does p53 induce cell-cycle arrest?

A

P53 prevents cells with faulty DNA dividing by activating cell cycle checkpoints. p53 upregulates p21, which binds to CDK1 or CDK2 to prevent entry into S-phase. This can be reversible of irreversible.
- p53 is involved in the G1/S as well as the G2/M cell cycle checkpoints.

29
Q

How does p53 help with DNA repair?

A

P53 regulates nucleotide excision repair. DNA-damaging agents upregulate p53 expression, which can promote expression of genes involved in DNA repair such as p53R2 and Gadd45 or interact directly with AP endonuclease and DNA polymerase.

30
Q

How does p53 block angiogenesis?

A

p53 alters the expression of genes that stimulate tumour angiogenesis.

31
Q

What is p53 regulated by?

A

Mdm2 E3-ubiquitin

32
Q

What does Mdm2 do to p53?

A
  • It keeps cellular p53 levels low by binding to its transactivation domain, preventing it from acting as a transcription factor.
  • Promotes p53 movement into the cytosol where it can be bound by ubiquitin to be degraded.
33
Q

How is apoptosis initiated in damaged cells?

A

Kinases are recruited to phosphorylate p53 to prevent Mdm2 binding (Mdm keeps p53 levels low) and initiates apoptosis.

34
Q

Other than Mdm2, what else regulates p53?

A

It can also be regulated by ARF binding to Mdm2 to prevent p53 degradation.

35
Q

What is RSV?

A

Rous sarcoma virus (RSV) is a virus shown to cause sarcomas following experiments in chickens.

36
Q

Briefly describe the experiment that showed that RSV was a virus shown to cause sarcomas in chickens

A

A sarcoma from a chicken was removed, ground up and filtered, and the cell-free extract injected into another chicken – where it caused a sarcoma. In vitro cells infected with RSV also displayed a change in phenotype such as loss of anchorage and contact inhibition

37
Q

How is RSV able transform primary fibroblasts?

A

RSV carries a tumorigenic factor

gene v-src

38
Q

What characteristics do transformed cells show?

A
  • Altered plasma membrane (blebbing)
  • Altered adherence (rounded and loss of monolayer)
  • Altered cell proliferation (high cell density and immortality)
39
Q

What are Proto-oncogenes?

A

Normal genes that promote cell growth that can become oncogenes when mutated. Oncogenes are cancer causing genes.

40
Q

Are most cancer-causing mutations of proto-oncogenes inherited or acquired.

A

Some cancer syndromes are caused by inherited mutations of the proto-oncogenes which cause activated oncogenes. But the majority of mutations are acquired.

41
Q

How are oncogenes activated?

A
  • Chromosome rearrangements
  • Gene duplication
  • Point mutation
42
Q

What are chromosomal rearrangements? Why can they cause oncogene activation?

A

Structural changes in the native chromosomes. Genes can be translocated to nearby promoters

43
Q

What is the problem with gene duplications

A

Having additional copies of a gene can lead to over-expressed proteins

44
Q

How do point mutations cause activation of oncogenes

A

Affecting the activity of a protein to prevent its normal regulation

45
Q

What are the three main types of oncogene activation?

A
  1. Increased protein concentration
  2. Increased enzyme or protein activity
  3. Regulation loss
    All of which lead to an excess in normal growth stimulating proteins
46
Q

Give an example of a mutated proto-oncogene

A

RAS

It undergoes hyperactivation due to regulation loss.

47
Q

What are RAS proteins?

A

Small GTPases that transmit signals, which control several cellular processes.

48
Q

What is the active and inactive RAS types?

A 
GTP-bound = active
GDP-bound = inactive
49
Q

How is RAS normally activated and inactivated?

A
  • GTP is hydrolysed by GTPase activity and GTPase-Activity Accelerating protein (GAPs).
  • GDP is then exchanged for GTP using Guanine Nucleotide Exchange Factors (GEFs) to activate Ras.
50
Q

What happens to RAS in mutated cells?

A

Ras is permanently active as the GTPase part is dysfunctional meaning cell division occurs uncontrollably.

51
Q

Why do TSG need two hits but oncogenes only need one?

A

Whilst tumour suppressor genes require a two-hit process to cause cancer due to a loss of function, oncogenes cause a gain in function meaning only one copy of the gene needs to be mutated.

52
Q

What are the three most clinically significant RAS proto-oncogenes?

A
  1. HRAS
  2. NRAS
  3. KRAS
53
Q

What 4 homologous RAS proteins are coded for by (HRAS, NRAS, KRAS) genes that display mutations in 20-30% of all tumours?

A

HRAS
NRAS
KRAS4A
KRAS4B

54
Q

What are the similarities and differences between HRAS, NRAS, KRAS4A, KRAS4B

A
  • same set of downstream effectors

- differences in their post-translational modifications cause differences in their signalling pathways

55
Q

What cancers are translocations mostly found in?

A

Leukaemias and lymphomas

56
Q

How do chromosomal rearrangements/translocation cause

A

It can a) combine a proto-oncogene with regulatory regions that enhance its function or b) combine two genes to encode a new protein with oncogenic function.

57
Q

What is Burkit’s lymphoma caused by?

A

MYC oncogene on chromosome 8 breaking away and joining to chromosome 14 (rarely chromosome 2 or 22). In its new location (which codes for Ig heavy chain H and light chains kappa and lambda) the oncogene’s promoter is replaced with that of the Ig chain without its protein coding region being affected. Ig promoters promote constant expression, which causes a loss in the regulation of the oncogenic protein which in turn causes inappropriate activation of other genes which eventually leads to the transformation of the cell.

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