Viral Oncogenesis Flashcards Preview

CMBM E4 CB > Viral Oncogenesis > Flashcards

Flashcards in Viral Oncogenesis Deck (40):

How do direct-acting oncogenic viruses work?
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The virus introduces a new 'transforming' gene into the host cell


What is an example of a direct-acting oncogenic virus?
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The src gene from RSV


How do indirect-acting oncogenic viruses work?
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The virus alters the expression of pre-existing (cellular) genes


What are onco-proteins?
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They interact with an inactivate cellular tumor suppressors.

ex. HPV proteins E6 and E7


T/F: There is a single mutation that causes cancer

False. Cancer is ALWAYS an accumulation of mutations


T/F: All persons infected with oncogenic viruses will get cancer

False. Typically pre-cancerous changes to cells are recognized by our immune system and cells are cleared out before cancer can establish


How do RNA tumor viruses work?

1. Carry transduced cellular oncogenes that play no role in virus replication
2. They act through indirect mechanisms


How do DNA tumor viruses work?

DNA viruses carry transforming genes that do NOT have homologs in the host genome (required for viral replication).

DNA virus oncoproteins interact with normal cellular proteins to alter their function.


The vast majority of human cancers of viral origin are due to ____ viruses.



Viral oncoproteins directly alter which cellular proteins?

Cell cycle regulators
Cytoskeletal proteins
Apoptotic pathways


What indirect mechanisms are involved in tumorigenesis?

Inflammatory pathways (generate ROS)
Immune suppression (leading to reduced clearance of aberrant cells)


What are types of HPV have a high oncogenic potential?

HPVs 16 and 18


How can DNA viruses take over the host cell's genome?

1. Some DNA viruses have an episome (genome outside the host genome)
2. Some can integrate into the host genome


What is the hallmark of cancers caused by HPV?

HPV cancers develop slowly (decades)
Chronic infection with high-risk HPV


What are the transformative oncoproteins in high risk HPV types?

E6 and E7


Identify the host cellular proteins that E6 and E7 bind to.

E6: p53
E7: pRb


How can E6 and E7 induce tumorigenesis?

All types of HPV have these genes, but the proteins behave differently in high-risk and low-risk types:

E6 protein binds to p53. Low risk HPVs make an E6 protein that binds to p53 with LOWER affinity than the E6 protein in high risk HPV.


What two proteins are critical checkpoints in the cell cycle?

p53 and pRb


What are the functions of p53?

Tumor suppressor
*Major control center of the cell cycle*
Arrests cell cycle at G1/S phase upon detection of DNA damage
Becomes active after phosphorylation, binds to DNA to trigger the expression of a variety of genes (transcription factor)


p53 mutations are indicated in ___% of tumors



What is MDM2?

p53 inhibitor


What happens when E6 binds p53?
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p53 cannot function as a transcriptional activator --> cell cycle progresses unregulated


Does inactivating p53 cause cancer?
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No. But it does lead to a slow accumulation of damaged DNA within the cell and its progeny. THIS can result in cancer.


What is pRb?

Tumor suppressor
Normally binds E2F transcription factor, which halts cell cycle
When pRb is phosphorylated/activated, it releases E2F, which then binds to DNA and begins transcription


What happens when E7 binds to pRb?
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Rb is stuck to E7, allowing E2F to transcribe genes unregulated.

Viral DNA is integrated, disrupts E2 expression, viral proteins are expresses and virus proliferates.


How are E6 and telomerase related?

E6 induces transcription of proteins which result in cellular increase in active telomerase


What is the major mechanism for KSHV infection?
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LANA1 (viral protein)
Binds to p53, blocks its transcriptional and pro-apoptotic activities


What are other major transforming mechanisms of KSHV?

Induction of chromosome instability
Dysregulation of cellular apoptotic pathways
Inducing secretion of growth factors


How does KSHV act indirectly?

Plays a systemic role in promoting tumor growth:
1. Immune evasion
2. Promotes angiogenesis by stimulating cytokine release from infected cells


What are the oncogenes implicated in EBV-caused tumorigenesis?



How does EBNA2 work?

Acts as a transcriptional activator for many downstream genes
--Viral: upregulates other late genes, activates viral promoter
--Host: upregulates B cell antigens CD21 and CD23

Can alter expression of host cell oncogene c-MYC


How does LMP1 work?

Constitutively active member of TNF receptor family

Looks like CD40, so can mimic B-cell activation and subsequent unregulated proliferation


What is the result of EBV-mediated transformation of LMP1?

Activates anti-apoptotic and cytokine genes, and cell surface proteins are altered

Changes B cell surfaces, making them easier to evade immune response


What chromosomal translocations to EBV tumors have in vivo, but not in vitro? What does this suggest?

c-myc proto-oncogene (8q24)
DO NOT show EBNA2 and LMP1

This suggests that the viral infection was required to begin the process of transformation, but that the translocation events in the host cell are the necessary factor in maintaining oncogenic status


What forms of cancers are commonly associated with retroviruses?



What are the hallmarks of retroviral infection?

Genetic material is inserted at random within the host genome
Viral genetic material remains within the cellular DNA for the life of the cell
No known way to cure a cell of chronic retroviral infection


How does an acute transforming retrovirus work?
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Virus carries an oncogene, which is then incorporated into the host genome under viral promoter


How do acute and slow transforming retroviruses differ?
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Slow transforming viruses do NOT carry an oncogene


Where does the oncogene in an acute transforming retrovirus come from?
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From the host. Typically an oncogene that was picked up by the virus --> becomes oncogenic under the viral promoter


What does tumor formation depend on in slow transforming retroviruses?

Can depend on WHERE the viral genome is inserted into host genome