.microbio E2: Oncogenic Viruses

Front 1

Differentiate between normal, immortalized, and transformed cells.

Back 1

Cells explanted from NORMAL tissues and grown in culture often require specific growth factors, attachment to a substrate, are contact inhibited, and will undergo only a limited number of cell divisions before senescing. IMMORTALIZED cells may retain many of these characteristics but will undergo unlimited cell divisions in culture. TRANSFORMED cells are immortal and have lost most if not all of the other restrictions (might grow unattached, no longer require specific growth factors, or are not contact inhibited).

Front 2

True or False:
Regarding retroviruses, once a typical retroviral provirus is integrated into host , no viral gene products are required to maintain or propagate the viral DNA sequences.

Back 2

TURE

Front 3

_____ are normal host genes that when mutated or altered in expression can lead to tumor formation.

A. oncogenes
B. proto-oncogenes

Back 3

proto-oncogenes

Front 4

Regarding direct oncogenic mechanisms of oncogenic RNA viruses (retroviruses), what is the difference between acutely transforming retroviruses and chronic transforming retroviruses?

Back 4

Acutely transforming retroviruses contain a copy of an oncogene that was originally derived from a host cell proto-oncogene. Transforming retroviruses have lost essential viral genes and thus they are defective viruses and cannot replicate without co-infection with a helper virus to supply the missing viral gene products. Transformation is quick and tumor induction is rapid, approaching 100% of every subsequent infection. Where integration occurs in the host genome, however, is more or less random and appears irrelevant. The proteins encoded by acutely transforming retroviruses are involved in signal transduction pathways that ultimately affect nuclear transcription factors and hence expression of genes that activate cell proliferation.

Chronic transforming retroviruses do NOT encode oncogenes. They are autonomous and able to replicate on their own, thoguh. Tumor development can take months to years and may only occur in a small percentage of infected hosts. Provirus is integrated at the same site in all cells in a given tumor.

Front 5

True or False:
While transformign retroviruses are found in many animal species, we are fortunate that no retroviruses having direct mechs of oncogenesis are known to infect humans.

Back 5

True. HTLV-1 has been show to cause cancer but it does so INDIRECTLY, not directly.

Front 6

Regarding direct oncogenic mechs of oncogenic DNA viruses, many DNA viruses achieve cell cycle release by interfering with two key cellular tumor suppressors that control cell cycle progression. Name em.

Back 6

pRB and p53

pRB binds to E2F and prevents it from activating genes that allow progression from G1 to S phase. By expressing proteins that bind to pRB with a higher affinity than pRB has for E2F, several DNA viruses release E2F from pRB / E2F complexes, freeing E2F to activate genes necessary to drive the cells into S phase.

p53: is a tumor suppressor that is up-regulated by DNA damage and stress. Expression of p53 also activates p21 promoter, that acts to block cell cycle progression. p53 also promotes apoptosis by upregulating expression of BAX, which blocks the anti-apoptotic activity of BCL-2.

Front 7

Under normal circumstances, pRB and p53 do what?

Back 7

pRB binds to E2F and prevents it from activating genes that allow progression from G1 to S phase. By expressing proteins that bind to pRB with a higher affinity than pRB has for E2F, several DNA viruses release E2F from pRB / E2F complexes, freeing E2F to activate genes necessary to drive the cells into S phase.

p53: is a tumor suppressor that is up-regulated by DNA damage and stress. Expression of p53 also activates p21 promoter, that acts to block cell cycle progression. p53 also promotes apoptosis by upregulating expression of BAX, which blocks the anti-apoptotic activity of BCL-2.

Front 8

What cell cycle control is being described?

binds to E2F and prevents it from activating genes that allow progression from G1 to S phase. By expressing proteins that bind to [X] with a higher affinity than [X] has for E2F, several DNA viruses release E2F from [X] / E2F complexes, freeing E2F to activate genes necessary to drive the cells into S phase.

Back 8

pRB

Front 9

What cell cycle control is being described?

is a tumor suppressor that is up-regulated by DNA damage and stress. Expression of [X] also activates p21 promoter, that acts to block cell cycle progression. [X] also promotes apoptosis by upregulating expression of BAX, which blocks the anti-apoptotic activity of BCL-2.

Back 9

p53

Front 10

Which two strains of HPV are associated with about 70% of cancers of the cervix?

Back 10

HPV 16 and HPV 18

High risk strains are also associated with oropharyngeal caners.

Front 11

What protein from HPV 16 and HPV 18 binds to and inactivates pRB?

A. E5
B. E6
C. E7

Back 11

C. E7

E6 binds to p53 and induces its degradation

Front 12

What protein from HPV 16 and HPV 18 binds to and degrades p53?

A. E5
B. E6
C. E7

Back 12

B. E6

E7 binds to and inactivates pRB

Front 13

Adenoviruses have no linked cancers to humans but some strains have been able to transform cells and become tumorigenic in some animal models. The adenovirus [ E1A / E1B ] protein binds to pRB and the [ E1A / E1B ] protein binds to p53. In both cases the bound proteins are no longer active.

Back 13

E1A binds pRB
and
E1B binds p53

Front 14

EBV infects what type of cell, where it establishes a latent state in which the viral genome is maintained as a circular episome (not integrated). Immortalization requires expression of several viral genes. What are those?

Back 14

EBNA-1 viral protin expressed constitutively when EBV is latent (not sufficient by itself to cause immortalization). But also needs the c-myc/ Ig translocation for immortalization.

EBV only indirectly contributes to cancer by providing a pool of rapidly dividing, immortalized B- cells, thereby increasing the odds that mutations in cellular genes necessary for cancer will occur.

Front 15

In EBV, protein ____ maintains the latent episome and in KSHV, protein _____ maintains the latent episome. Detail how both are indirect contributors to oncogenesis.

Back 15

In EBV it is EBNA-1 ; in KSHV it is LANA.

EBNA-1 is very resistant to protease processing so its peptides are not presented to MHC I. Thus it allows the infection to go undetected. Thus it indirectly contributes to cancer by providing a pool of rapidly dividing, immortalized B cells, thereby increasing the odds that a cancerous mutation might occur.


KHSV's LANA binds and inactivates p53 and pRB. Without those two cellular control mechanisms, there is higher propensity to develop cancer.