Lecture 4 & 5 (tumorigenic RNA viruses) Flashcards
Three families of retroviruses
- Oncoviruses (oncongenic viruses)
- Lentiviruses (slow viruses)
- Spumaviruses (foamy viruses)
How do retroviruses replicate?
via a DNA intermediate or provirus which integrates into host DNA
What viral protein is important for proviral integration into the host genome?
integrase
3 principal viral genes
Gag, Pol, Env
What does Gag code for?
the virion’s structural proteins
What does Pol code for?
reverse transcriptase enzyme (copies RNA into DNA)
What does Env code for?
the virus’s envelope proteins
Two groups of oncogenic viruses
Group I: long latency transforming
Group II: acutely transforming
How do long latency transforming retroviruses perturb host genome expression?
because of the provirus location in the genome (insertional mutagenesis)
Example of a long latency transforming retrovirus
mouse mammary tumour virus (MMTV)
Do long latency transforming retroviruses carry an oncogene?
No
The most frequent site of ALV DNA integration in lymphomas is between…
exons 1 and 2 of c-myc proto-oncogene
MMTV proviral DNA is integrated downstream of __ in mammary carcinoma
int-1
Oncogenes discovered by insertional mutagenesis
- myc (transcription factor)
- ALV - ErbB/EGFR (RTK)
- ALV - int-1 (growth factor)
- MMTV
When ALV infects a cell and by chance integrates close to the src gene, the resulting virus contains part of src gene and is called __
Rous sarcoma virus (RSV)
What is the only acutely transforming retrovirus known to carry the src oncogene in addition to its full complement of viral genes (gag, pol, env)?
Rous sarcoma virus (RSV)
Acutely transforming retroviruses are derived from…
long latency retroviruses (have transduced a cellular oncogene)
How do acutely transforming retroviruses cause cancer?
Due to aberrant expression or qualitative changes to the transduced gene (i.e. the gene that they’ve picked up)
What do acutely transforming retroviruses usually require to replicate?
a ‘helper virus’ from Group I
Examples of acutely transforming retroviruses and their oncogene
- RSV (src)
- FBJ-MSV (fos, expressed as an independent translation product of full length viral RNA)
- Ab-MuLV (abl, expressed as a gag fusion protein)
- AEV ES4: ErbA (expressed as a gag fusion protein) and ErbB (translated independently from spliced mRNA)
What receptor does ErbA encode?
Thyroid hormone receptor
__ oncogene is a receptor tyrosine kinase
Kit
Differences between retroviral oncogenes (v-oncs) vs cellular oncogenes (c-oncs/proto-oncogenes)
- Much higher level of expression (quantitative change)
- Contain no introns (qualitative change)
- Structural differences e.g. fusion protein with gag
- Point mutations (very common)
Point mutation → v-Ras
One amino acid change at position 12 for example causes Ras to be constitutively active (GTP-bound)
Mutations in RSV src gene
- Deletion of 19 C-terminal amino acids enhances tyrosine kinase activity
- Several amino acid substitutions will increase the protein activity → increased expression of src
