Lecture 28 - Oncogenic Viruses Flashcards

1
Q

Three classes of cancer-causing agents

A

1) Chemical carcinogens
2) UV and ionising radiation
3) Viruses

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2
Q

Carcinoma

A

Tumour of epithelial origin

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3
Q

Sarcoma

A

Tumour of fibroblasts

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4
Q

Tumours of leukocyte origin

A

Lymphoma (when solid)

Leukaemia (when circulating)

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5
Q

Are most cancers mono- or polyclonal?

A

Monoclonal

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6
Q

Some characteristics of transformed cells
1)
2)
3)

A

1) Lack of contact inhibition of growth
2) Lack of dependence on exogenous growth factors
3) Lack of anchorage dependence on some cell types

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7
Q

What happens in G1?

A

Synthesis of proteins required for DNA synthesis

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8
Q

When is DNA replicated?

A

S phase

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9
Q

What happens in G2 phase?

A

Synthesis of proteins for daughter cells

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10
Q

When is the restriction point in the cell cycle?

A

G1

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11
Q

What determines whether a cell stops at, or progresses beyond the restriction point in the cell cycle?

A

Environmental cues

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12
Q

C-onc

A

Cellular oncogenes or proto-oncogenes

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13
Q

V-onc

A

Viral-oncogenes.

Can be a host oncogene, modified host oncogene, or a novel viral protein

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14
Q

Examples of tumour suppressor genes

A

Retinoblastoma, p53

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15
Q

Four main classes of oncogene

A

1) Growth factors
2) Growth factor receptors
3) Intracellular signal transducers
4) Transcription factors

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16
Q

20% of human cancers are associated with what?

A
Human T cell leukaemia virus type 1
Hepatitis C virus
Human papilloma virus
Epstein-Barr virus
Hepatitis B virus
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17
Q

RNA viruses associated with human cancers

A

Human T cell leukaemia virus type 1 (retrovirus)

Hepatitis C virus (flavivirus)

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18
Q

DNA viruses associated with human cancers

A

Human papilloma virus (papovavirus)
Epstein-Barr virus (herpesvirus)
Hepatitis B virus (hepadnavirus)

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19
Q

Are retroviruses lytic?

A

No

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20
Q

If a retrovirus carries an oncogene, what type is it?

A

V-onc that has a C-onc counterpart

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21
Q

What does retroviral transformation often involve?

A

Stimulating activators of cell cycle

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22
Q

Are oncogenic DNA viruses lytic?

A

Yes, normally

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23
Q

Type of V-onc often carried by DNA viruses

A

A unique viral product. No C-onc

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24
Q

What does DNA viral transformation often involve?

A

Inactivation of cell-cycle inhibitors

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25
Q

Two types of oncogenic retroviruses

A

Endogenous and exogenous

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26
Q

Normal retroviral proviral genome

A

LTRs flanking gag, env, pol

27
Q

Defective oncogenic retroviral genome

A

LTRs flanking gag, env, pol, but an oncogene is disrupting one of the gag, env or pol

28
Q

Replication-competent oncogenic retroviral proviral genome

A

LTRs flanking gag, env, pol, with an oncogene that isn’t disrupting gag, env or pol

29
Q

Example of a replication-competent oncogenic retrovirus

A

Rous sarcoma virus

30
Q

Three mechanisms of tumour production by exogenous retroviruses

A

1) Transducing (acute transforming)
2) Cis-activating (non-acute transforming)
3) Trans-activating

31
Q

Transducing retroviruses

A

Introduce a v-onc gene under LTR transcriptional control into host genome

32
Q

Cis-activating retroviruses

A

Insertional mutagenesis.

Doesn’t carry a v-onc gene, but upon integration LTR drives expression of a C-onc gene

33
Q

Trans-activating retroviruses

A

Contains a gene-regulation protein that drives tumour growth

34
Q

Type of tumours produced by transducing retroviruses

A

Polyclonal

35
Q

State of most transducing retroviruses

A

Replication defective.

Except for Rous sarcoma virus

36
Q

Are transducing retroviruses found in humans?

A

No. Rous sarcoma virus is a virus of chickens

37
Q

How can insertional mutagenesis drive tumour growth?
1)
2)

A

Either:

1) Proviral LTR can act as a promoter for c-onc in cis with provirus.
2) Provirus unwinds DNA upstream of c-onc, acts as a transcriptional enhancer

38
Q

Best-studied cis-acting retrovirus

A

Murine leukaemia virus

39
Q

Examples of cis-acting retroviruses

A

Murine leukaemia virus

Koala retrovirus

40
Q

Example of a trans-acting retrovirus

A

Human T-cell lymphotropic virus type 1 (HTLV-1)

41
Q

What is human T-cell lymphotropic virus type 1 associated with?

A

Adult T-cell leukaemia-lymphoma

42
Q

How is human T-cell lymphotropic virus type 1 transmitted?

A

Placenta, breast feeding, sexual intercourse, contaminated needles

43
Q

Effects of human T-cell lymphotropic virus

A

Virus persists for life, often causing no disease.

After 20-40 years, a small proportion of those infected develop adult T-cell leukaemia-lymphoma

44
Q

What does HTLV infect?

A

CD4+ T cells

45
Q

Regulatory proteins in HTLV

A

Tax, rex

46
Q

Tax
1)
2)
3)

A

1) Regulatory protein in human T-cell lymphotropic virus.
2) Transcription factor that acts on the LTR region, but also can act on C-onc genes in the host genome.
3) Also acts to upregulate IL-2, IL-2R transcription, to promote T cell proliferation

47
Q

HTLV protein involved in oncogenesis

A

Tax

48
Q

Why do some DNA viruses lead to oncogenesis?

A

Need host cell to be in S phase so that genomes can be replicated. Most cells are in G0 or G1.
Early proteins are normally encoded to get host cell into S phase

49
Q

Features of DNA stimulated tumours
1)
2)
3)

A

1) Limited viral protein expression.
2) Early gene expression
3) Can show integration of viral genome or episome

50
Q

Function of retinoblastoma susceptibility gene

A

Controls transition from G1 to S.
In hypophosphorylated active form sequesters E2F family of transcription factors, preventing them from driving the cell cycle forward

51
Q

Function of p53

A

Transcription factor that induces expression of proteins that arrest cell growth and initiate apoptosis in response to DNA damage

52
Q

Proportion of human tumours that have a mutation in the p53 gene

A

50%

53
Q

Examples of viral strategies for suppressing p53 function
1)
2)

A

1) Hep C binds a protein to p53, prevents nuclear localisation
2) Papilloma viruses mark p53 for degradation

54
Q

HPV seotypes that lead to carcinoma

A

HPV-16 and -18

55
Q

HPV E6 protein

A

Marks p53 for degradation

56
Q

HPV E7 protein

A

Inhibits retinoblastoma susceptibility protein

57
Q

What happens in papillomavirus oncogenesis?

A

HPV is randomly integrated into host genome. E2 protein is lost, which normally negatively represses E6 and E7 proteins

58
Q

Type of cancer linked to hep B

A

Hepatocellular carcinoma

59
Q

Proportion of those infected with hep B that develop hepatocellular carcinoma

A

2-10% of patients

60
Q

How does hep B lead to hepatocellular carcinoma?
1)
2)

A

1) Random integration of episome into host genome.
Transactivating gene X can deregulate a nearby C-onc (src tyrosine kinase).
2) Repeated destruction and regeneration of hepatocytes can lead to accumulation of mutations

61
Q

Increase in hepatocellular carcinoma risk when infected with hep C

A

100x increase in risk

62
Q
Cancers associated with EBV
1)
2)
3)
4)
A

1) Burkitt’s lymphoma (Africa)
2) Nasopharangeal cancer (common in China, SE Asia)
3) B cell lymphomas in immunosuppressed patients (EG: AIDS patients)
4) Detected in ~40% of Hodgkin’s lymphoma patients

63
Q

Burkitt’s lymphoma genesis

A

Translocation of C-myc (chromosome 8) to a part of chromosome 14 which is under transcriptional control of a promotor for Ig heavy chain production

64
Q

Role of EBV in Burkitt’s lymphoma

A

EBV transforms B cells, leading to uncontrolled expansion.

Enhances effects of mutations such as C-myc translocation from Chr.8 to Chr.14