Tumour viruses and carcinogenesis Flashcards
What proteins are likely to be encoded for by late viral genes?
Proteins involved in the packaging of the viral progeny
What is a common feature of viral genomes, given the amount of genetic information being packed into a small particle.
Overlapping of genes
By what mechanism do viruses induce cellular proliferation?
If the early genes of the viral genome are transcribed but the late genes are not (damaged?) then there is a latent, persistent infection; the cells don’t produce any viral progeny so won’t be killed. But, the early genes that are transcribed may induce cellular proliferation
How do DNA tumour viruses integrate into host cells?
Virus needs to activate S phase of the cell cycle to replicate viral DNA in the nucleus. Viral genomes integrate into host DNA.
What occurs if their is full replication of viral genomes?
Cell death
What occurs if there is defective virus keeping early genes or non permissive cells only expressing early genes
There will be cellular transformation
Different proteins of oncogenic viruses target common cellular pathways. Give examples of these pathways
- Block p53
- Sequester Rb
- Signal transduction
- Tyrosine kinase signalling
What is the main effect of the E6 viral protein
Degrade p53 - but has pleitropic effects
How does hepatitis C virus cause oncogenic mutations in liver cells?
Destroy mature hepatocytes which stimulates their regeneration from stem cells that may carry oncogenic mutations
What is the gag retroviral protein responsible for?
It wraps up the genome of the virus
What is the env retroviral protein responsible for
Protein responsible for forming the viral envelope.
What is the pol retoviral gene responsible for>
Produces enzymes required for RNA reverse transcription and integration into the host genome (reverse transcriptase and integrase, protease which chops up gag proteins which form the protein core).
What are the long terminal repeats at the 3’ and 5’ ends of the retroviral genome responsible for?
Contain promoter and enhancer sequences for switching on genes.
Why might the LTR be responsible for inducing an oncogenic switch in a host cell
- As the viral genome is integrated into the host chromosome, the LTR will induce the expression of host genes immediately downstream of the viral genome. If this an oncogene then this cell will proliferate. This requires a long, latent infection as the point of integration of the viral genome is random.
- If a host oncogene becomes spliced into the viral genome, whilst maintaining the gag, env gene, then the now viral oncogene will be part of the viral genome, and be passed on to its progeny. This is an acutely transforming retrovirus that can infect and transform host cells subsequently.
Where does cervical cancer develop?
At the transition zone between columnar and squamous epithelium.
What type of cell do cervical cancers tend to be
Squamous
where are early and late genes expressed in HPV positive cervical cancer
Early genes are expressed in the basal layer. Late genes are expressed in differentiated squamous cells.
Characterise adult T-cell leukaemia and HTLV-1
A retroviral malignancy of CD4+ and CD25+ T-cells. Commonest adult leukaemia in Japan. Caused by HTLV-1 infection decades before appearance of tumour and is transmitted via milk or leukocytes. Prevention therefore came from screening pregnant women and blood donors.
How does HTLV-1 induce tumorigenesis?
Extra genes, tax and HBZ are essential for the development of the malignancy. These are transactivators which act backwards to induce expression of both the viral genome and cellular oncogenes.
What is a co-factor for liver cancer? (HBV infection)
Aflatoxin - HBV infection and aflatoxin causes a 5-fold increase in relative risk of developing liver cancer
What is the relationship of EBV and Burkitts lymphoma?
EBV infection and BL occur in regions of endemic malaria, particularly in boys with tumours of the jaw during secondary dentition.. Malaria acts as a co-factor, immunosuppressing individuals and inducing B-cell production. Coupled with EBV infection; C-myc translocation occurs to Ig heavy or light chain. C-myc is downstream of the highly active promoter in lymphoid cells which causes B cell proliferation and the resultant tumour
What effect does immune deficiency have on virus linked cancers
Increase
How do KSHV and HIV cause KS
primary cause is KSHV. HIV immunosuppresses patients and increases the potential of a transforming KSHV infection
What kind of viruses are Merkel cell polyomavirus, HBV, SV40, HPV?
Small DNA tumour viruses
What kind of viruses are KSHV and EBV?
Large DNA viruses - the episome contains >70 genes which contain enzymes requirede for viral DNA replication
What kind of viruses are HTLV-1 and HCV?
Retroviruses
What is the life cycle of a retrovirus?
Soon after infection, the viral genome is transcribed by a virion associated enzyme, reverse transcriptase into a double stranded DNA copy. This is integrated into host chromosomal DNA using viral integrase. The integrated provirus is similar to a cellular gene except transcription is initiated at the viral LTR.
Is infection by a retrovirus temporary for a cell?
No - usually lasts the lifetime of the cell as the provirus cannot be removed from the host chromosomal DNA.
What pathways do the HCV core proteins interact with?
14-3-3 leads to RAF activation
p53 inactivation
p21 inhibition
Wnt upregulation leads to cell growth.
