Viral Oncogenesis Flashcards
Common traits of human viral oncogenesis
- Oncoviruses are necessary but not sufficient for cancer development - most people who are infected do not develop cancer from the virus
- Viral cancers appear in the context of persistent infections and occur many years to decades after acute infection
- The immune system can play a deleterious or a protective role in virally induced oncogenesis
How do viruses cause cancer INDIRECTLY
Chronic inefction causes cirrhosis, inflammation, tissue damage, high levels of cell division. This cycle vastly increases the probability that hepatocytes will develop mutations and chromosomal aberrations that derail their growth control
How do viruses cause cancer DIRECTLY
Upon infection, some DNA viruses stimulate the cells to enter S phase of the cell cycle and ready themselves for DNA synthesis. The virus needs this environment for its own replication. If the infected cell is not killed, the same viral proteins can continue to direct the cell to override normal controls on cell growth
Viruses most clearly associated with human cancer
Hepatitis B: hepatocellular carcinoma
Hepatitis C: hepatocellular carcinoma
EBV: lymphoma; nasopharyngeal carcinoma
HHV8: Kaposi’s sarcoma KSHV
HTLV: adult T cell leukemia
HPV: cervical cancer; head and neck cancer
Merkel Cell Carcinoma
Aggrressive skin cancer in elderly and immunosuppressed patients
Papillomavirus characteristics
- Member of the papovavirus family
- Infect cutaneous and mucosal epithelia hands, feet, anogenital tract
- Small circular, double stranded DNA genome
- Many subtypes (about 100)
- 1/3 subtypes infect genital tract (sexually transmitted)
Early and Late genes encoded by virus
- E1 and E2 mediate the replication and transcription of the viral DNA
- E4 disrupts cytokeratins to facilitate virus egress
- L1 and L2 compose the capsid
- E5 stimulates constitutive growth factor receptor signaling
- E6 and E7 neutralize the major “brakes” that regulate the cell cycle - p53 and Rb - and hence uncouples cell division from key regulatory controls
Which viral encoded genes are associated with oncogenesis
E5, E6, E7
Course of Papillomavirus infections
Papillomavirus ⇒ Inoculation of epithelium ⇒ Hand, foot, throat, or cervix ⇒ Local multiplication ⇒ Wart ⇒ Resolution (latency)/Cell transformation
How does HPV affect the epithelium
HPV stimulation of cell cycle causes cells in the stratum spinosum to replicate. Normally, only the stratum basale cells replicate
What are CDKs and how are they regulated
Cyclin dependent kinases move the cell cycle ahead by phosphorylating key substrates
Regulated in many ways:
- Temporally regulated synthesis
- Proteasome-mediated degredation of their cyclin subunits
- Stimulatory and inhibitory phosphorylation events
- Stoichiometric inhibitors
Rb protein
A key “brake” that blocks progression into the S phase
When sufficient Cdk/cyclin has accumulated in G1, Rb becomes phosphoryalted and inactivated and the cell can move into S phase
How is E7 a key regulator of cell cycle progression
The E7 protein binds to Rb, targets it for proteosomal degradation, and so prevents it from blocking the progression to S phase
How is E6 a key regulator of cell “accuracy’’ and why is it important in cellular immortality
- E6 protein recruits a ubiquitin ligase that targets p53 for degradation and therefore prevents it from blocking the progression to S phase or inducing apoptosis
- E6 protein induces the expression of telomerase, which enables cells to maintain their chromosomal telomeres and avoid senescence
What does p53 do?
“guardian of the genome”
Activated by innapropriate entry into cell cycle
Induces the production of Cdk/cyclin inhibitors, and stops the cell cycle - major inducer of apoptosis
LSIL:
HSIL:
CIN:
LSIL: Low grade squamous intraepithelial lesion
HSIL: High grade
CIN: Cervical intraepithelial neoplasia
