Oncogenic Viruses Flashcards
(92 cards)
1
Q
What percentage of all human cancers are caused by viruses?
A
15-20%.
2
Q
Viruses are the leading cause of what 2 types of cancers?
A
Cervical and liver cancers.
3
Q
How do viruses cause cancer?
A
Alter the control of cell proliferation.
4
Q
What are 3 ways viruses alter the control of cell proliferation?
A
- Activate signaling pathways to stimulate constitutive growth
- Release cell cycle control to allow uncontrolled growth
- Infected cell destruction/clearance leads to unplanned regeneration
5
Q
Is cancer necessary for oncogenic virus replication to take place?
A
No.
6
Q
Are viruses generally produced from malignant tumors?
A
No.
7
Q
What is an alternative to lytic replication for oncogenic viruses?
A
Cancer induction: more specifically cell transformation.
8
Q
T or F. In humans, cancers occur shortly after oncogenic virus infection.
A
F: long after infection.
9
Q
Virus-caused cancers occur more frequently in what patient population?
A
Immunocompromised patients.
10
Q
Is the presence of a virus genome in tumor cells sufficient evidence of an oncogenic virus-caused cancer?
A
No: may be coincidental and need to rule out contamination.
11
Q
What are the 4 epidemiologic criteria for a virus to be considered an oncogenic virus?
A
- Coincident geographic distribution of infection, cancer
- Higher incidence of viral markers in tumors vs. control references
- Viral markers should precede the cancer
- Reduction of infection rates should reduce the cancer
12
Q
What are the 3 virologic criteria for a virus to be considered an oncogenic virus?
A
- Virus should transform cells in vitro
- Virus genome present in tumor cells but not normal cells
- Tumor induction in experimental animals
13
Q
What are the 6 known human cancer viruses?
A
- Human T-lymphotropic virus type 1 (HTLV-1)
- Human herpesvirus 8 (Kaposi’s sarcoma-associated herpesvirus aka KSHV)
- Epstein-Barr virus (EBV)
- Human papillomavirus (HPV)
- Hepatitis B virus (HBV)
- Hepatitis C virus (HCV)
14
Q
What 3 DNA viruses are known to transform cells and/or cause tumors in animals but have not yet been linked to a human cancer?
A
- Adenovirus
- Polyomavirus
- Poxvirus
15
Q
What is an immortalized cell?
A
A cell that retains its original properties but grows indefinitely.
16
Q
What is a transformed cell?
A
A cell that is immortalized but loses many growth properties
17
Q
What 5 growth properties do transformed cells lose?
A
- Reduced need for serum growth factors
- Loss of contact inhibition
- Anchorage independent (can grow in soft agar)
- Appear round as opposed to typical morphology
- May cause tumors when introduced into suitable animal
18
Q
What are the 2 earliest discovered retroviruses (RNA tumor viruses)?
A
- Avian leukemia virus (1908)
2. Rous sarcoma virus (1911: first solid tumor virus)
19
Q
T or F. Retroviruses efficiently transform cells, cause rapid cancers, and kill host cells in the process.
A
F: they did not kill host cells.
20
Q
What is the name of the oncogene in the retrovirus genome?
A
V-oncogene.
21
Q
What are v-oncogenes derived from?
A
Cellular oncogenes (c-oncogenes or proto-oncogenes.
22
Q
Where did v-oncogenes come from?
A
Picked up by ancestors as a result of integration of viral genome into host chromosome during normal replication cycle of retroviruses.
23
Q
What 3 groups are retroviruses classified into?
A
- Transducing oncogenic viruses
- Non-transducing oncogenic viruses
- Non-transducing, long latency oncogenic viruses
24
Q
What is an example of a transducing oncogenic virus?
A
Rous sarcoma virus.
25
What is an example of a non-transducing, long latency oncogenic virus?
HTLV-1.
26
What are the 3 characteristics of transducing oncogenic viruses?
1. Contain v-oncogene
2. 100% rate of tumor formation
3. Rapid tumor formation w/in days
27
What are the 3 characteristics of non-transducing oncogenic viruses?
1. No v-oncogene but can activate c-oncogene via integration
2. High rate of tumor formation
3. Tumor formation w/in weeks to months
28
What are the 3 characteristics of non-transducing, long latency oncogenic viruses?
1. Contains a v-oncogene unrelated to c-oncogenes
2. Low (<5%) rate of tumor formation
3. Tumor formation w/in months to years
29
RNA and DNA tumor viruses transform cells by what mechanism?
Activation of signaling pathways.
30
What 2 ways do RNA and DNA tumor viruses stimulate cell division?
1. Increase/dysregulation of kinase cascades that increase gene expression related to cell division
2. Introduce new transcription factors to upregulate gene expression
31
V-oncogenes control signal transduction related to what?
Cell growth and regulation.
32
What are 6 things utilized by v-oncogenes?
1. Tyrosine kinases
2. Tyrosine kinase growth factor receptors
3. Serine/threonine kinases
4. Transcription factors
5. Hormone receptors
6. G proteins
33
How do v-oncogenes differ from c-oncogenes? What does that result in?
V-oncogenes are always active. This results in loss of signaling control and inappropriate growth.
34
What property of v-oncogenes is essential for its function?
To stimulate unregulated growth, it is essential that v-oncogenes are always active.
35
Are there any human examples of transducing retroviruses that cause cancer?
No.
36
How do non-transducing retroviruses operate?
By insertional activation.
37
What is insertional activation?
Virus genome or part of the genome randomly inserts into host chromosome or strong promoters or transcriptional enhancers located in the virus genome lead to an unregulated overexpression of nearby c-oncogenes.
38
Are integration events next to c-oncogenes and subsequent alterations that lead to increased expression common or rare?
Rare.
39
What is the lag time for tumor induction caused by non-transducing retroviruses?
Intermediate to long lag time.
40
Are tumors caused by non-transducing retroviruses monoclonal or polyclonal?
Monoclonal.
41
What cancers does HTLV-1 cause?
Adult T cell leukemias and lymphomas (which is an aggressive non-Hodgkin's lymphoma that is fatal).
42
What cell type does HTLV-1 infect and transform?
CD4+ T cells.
43
What oncogene does HTLV-1 express that allows it to infect and transform CD4+ T cells?
Tax.
44
How does Tax accomplish its function?
Tax stimulates Ikk complex. Causes IkB degradation. Frees NF-kB to direct transcription in T cell nucleus. Immortalization and subsequent transformation of the T cell.
45
EBV is what type of virus?
DNA herpesvirus.
46
EBV is latent in what type of cell?
B cells.
47
EBV causes what types of cancers?
Burkitt's lymphoma, Hodgkin's lymphoma, posttransplantation lymphoma, and nasopharyngeal carcinoma.
48
What multi-spanning transmembrane protein does EBV encode for?
Latency Membrane Protein-1 (LMP-1).
49
How does LMP-1 differ from normal plasma membrane signaling proteins?
It oligomerizes independent of ligand and is always active.
50
What does LMP-1 activate and what does that result in?
Activates a kinase cascade. Localizes NF-kB to B cell nucleus. Leads to B cell immortalization.
51
What diseases does human herpesvirus 8 (KSHV) cause?
Kaposi's sarcoma, pleural effusion lymphoma, and Castleman's disease.
52
KSHV encodes what potential oncogenes? What do those oncogenes stimulate?
Cytokine and chemokine homologues that stimulate transformation.
53
What is the most significant oncogene that KSHV encodes for?
vGPCR.
54
What does vGPCR induce?
Growth and transformation.
55
How does vGPCR differ from cellular GPCRs?
It is always active.
56
Why is vGPCR always active?
Amino acid substitutions.
57
Simian virus 40 (SV40) is what type of virus?
DNA polyomavirus.
58
Is SV40 a human pathogen?
No.
59
SV40 was found in early preps of what?
The live polio vaccine.
60
SV40 encodes 2 versions of what?
Transforming antigen (T antigen).
61
What does T antigen function in?
Replication of the viral genome.
62
What does small T (sT) antigen bind to?
Phosphatase 2A, a serine/threonine phosphatase abundant in cells.
63
What does the binding of sT antigen to phosphatase 2A result in?
Inactivates phosphatase 2A. Increases the half-life of phosphorylation events. Uncontrolled stimulation of cell division results.
64
In regards to kinase (phosphorylation) cascades, how does SV40 differ from other oncogenic viruses?
Other oncogenic viruses upregulate the cascade, SV40 functions to sustain the cascade longer.
65
T or F. DNA tumor viruses inactivate tumor suppressor genes.
T.
66
What does the process of TSG inactivation by DNA tumor viruses involve?
Involves viral proteins required for viral replication.
67
Is the inactivation of TSG required for DNA tumor virus replication?
No: inactivation of TSGs is a side effect.
68
T or F. In additon to the sT antigen, SV40 also produces a large T (LT) antigen.
T.
69
What does expression of LT inhibit?
The negative regulation of the cell cycle.
70
What happens when LT binds Rb?
Binds to Rb protein. Rb is inactivated. Induces E2F-dependent transcription and cell division.
71
What happens when LT binds p53?
Binds to p53 protein. p53 is inactivated. Prevents apoptosis.
72
What type of replication does HPV undergo in permissive cells?
Lytic replication.
73
What does HPV do to non-permissive cells?
HPV transforms non-permissive cell but does not replicate in them.
74
HPV genotypes 6 and 11 cause what?
Warts which are benign tumors.
75
HPV genotypes 16, 18, and 35 cause what?
Cervical, penile, and oral cavity/throat cancers.
76
T or F. HPV is closely related to SV40 and other polyomaviruses.
T.
77
What proteins do HPV encode for that are necessary for virus replication?
E (early) proteins.
78
What happens to part of the HPV genome in metastatic tumors?
It is integrated into the host chromosome.
79
Integration of the HPV genome into host cell DNA disrupts what causing what?
Integration disrupts a viral regulatory gene, E2, which normally decreases expression of E6 and E7 early proteins. This results in high levels of E6 and E7.
80
In high risk HPVs, what does E6 bind to and what does this cause?
E6 binds p53 leading to p53 degradation.
81
In high risk HPVs, what does E7 bind to and what does this cause?
E7 binds Rb leading to Rb inactivation.
82
What cyclin homologue does KSHV produce?
V-cyclin.
83
What does v-cyclin bind to and what does that cause?
Binds to cyclin-dependent kinase 6 (CdK6) and activates it.
84
In regards to the cell cycle, what does the v-cyclin:CdK6 complex do?
Cell cycle progression is maintained (rather than regulated).
85
T or F. The v-cyclin:CdK6 complex is immune to inhibition by CdK inhibitors such as Cip or Ink4.
T.
86
T or F. Some viruses are known to cause cancer without directly altering cell division pathways.
T.
87
HBV and HCV are the leading cause of what type of cancer?
Hepatocellular carcinoma.
88
How do HBV and HCV cause hepatocellular carcinoma?
Long term (decades) chronic infection of liver by either virus. The constant clearance of infected hepatocytes may induce mutations that cause hepatocytes to proliferate uncontrollably.
89
What protein does HBV encode for that transforms cells?
Protein X, a liver-specific transcription factor that may play a key role in dysregulation of cell division.
90
Is EBV directly responsible for Burkitt's lymphoma?
No: BL arises from chromosome translocations. EBV encodes proteins that lead to immortalization of cells.
91
The translocation event in Burkitt's lymphoma does what?
Places c-myc under the control of a very powerful immunoglobulin heavy chain promoter leading to overexpression of c-myc.
92
Overexpression of c-myc leads to what in Burkitt's lymphoma?
Leads to further loss of cell division control.
