3-viral oncogenesis Flashcards
all cancers associated with viral infections are…
mistakes or byproducts of viral replication or gene expression
viruses that participate in tumorigenesis
retroviruses , papillomaviruses
how do viruses cause cancer?
inject DNA into cells , cause mutation
what is included in structure of simple retrovirus
RNA genome, envelope, Gag, Pol
Envelope consists of
surface glycoprotein, transmembrane protein
Pol consists of
integrase, reverse transcriptase
Gag consists of
Matrix, capsid, nucleocapsid
What is the gene of retrovirus
LTR, gag, pol, env, LTR
LTR
long terminal repeat that serves as promoter sequences for transcription of the reverse transcriptase gene
where are LTRs
3’ and 5’ end
how does retroviruses replicate
virus RNA is translated into DNA after entry into host through reverse transcriptase
-the translated DNA is integrated into host chromosome where it remains
steps of retrovirus infection
- retroviral particle attaches to cell surface
- endocytosis
- uncoating of nucleocapsid
- reverse transcriptase integrates the provirus into the host DNA
- assembly of infected mRNA –> proteins
2 classes of retroviruses
simple
complex
example of simple
feline leukemia
example of complex
bovine leukemia
what did hubner and todaro hypothesize
-cancer is caused by activation via mutation or inappropriate expression of a normal cellular gene
activated cellular gene
oncogene
normal cellular gene
proto oncogene
2 mechanisms for simple retroviruses
transduced by retroviruses (oncogene capture)
activated by an integrated provirus
what is retroviruses transduce cellular oncogenes
-retrovirus combines with oncogene and carries it in the viral genome
-make genome unfunctional and has to give up one of the functional units
how does simple retrovirus acquire a cellular proto oncogene
recombination
what allows simple retroviruses transduce cellular oncogenes
requires a helper virus that contains all the functional units to rescue the virus and allow replication
essential viral coding sequence is replaced by cell derived oncogene sequence. so these retroviruses are ___________
defective in replication
how can simple retrovirus transduction cause cancer
- mutated gene so that the protein is constitutively active
- inappropriately expressed or overproduced
how do simple retroviruses integrate oncogenes
LTR activates oncogene
precursor to transduced oncogenes
what indicates that tumors arose from a single cell mutation?
in tumors, the provirus is always found at the same site in the cell
-but the retrovirus can be integrated anywhere in the host cell genome
what is the site of retrovirus integration?
promoter regions or enhancer insertion
how do retroviruses integrate at the promoter insertion
retrovirus integrates near oncogenes allowing 5’ end or 3’ end of oncogene to fuse with LTR of retrovirus which activates it
-viral and cellular transcripts duse
how do retroviruses integrate at the enhancer insertion?
-presence of retrovirus will inc. expression of oncogene due to powerful LTR
-viral and cellular transcripts are not fused
could these same proto oncogenes be involved in non viral associated cancers
yes
where do oncogenes activated by simple retroviruses fit in the cell cycle
M phase to begin cell cycle
mitogenic signals
how do complex retroviruses cause cancer
deregulation of host genes involved in proliferation like cytokines and functional inactivation of p53 due to virus in lymphocyte
what is unique about complex retroviruses with cancer?
viral expression is seen at low levels in lymphocytes but no viral gene expression occurs in the tumor
-there is no virus in tumor
what allows complex retroviruses to cause cancer
TAX; viral transcriptional trans-activator and functions to make lots of viral RNA
TAX affects:
-activate transcription
-activate cytokines
-inactivate p53
-cause genomic instability
where do oncogenes activated by complex retroviruses fit in the cell cycle ?
Simple retroviruses: activate mitogenic signals and start cell cycle –> M phase
Complex: TAX, represses DNA repair and inactivates p53 –> G1-S
what are papillomaviruses ?
small non-enveloped DNA viruses that contain simple genome
-lytic viruses that normally cause warts can result in invasion cancers
what is unique about papillomavirus replication
intimately linked to tissue differentiation
-only select viral genes are expressed in cells that are at a specific stage of differentiation
-the terminally differentiated cell is the only cell that produces virus
how do papillomavirus cause cancer
contain viral genes that sequester tumor suppressor genes (p53, Rb)
how do papillomaviruses inactivate p53
has E6 that binds to p53 resulting in ubiquitination and degradation
-leads to loss of genome maintenance functions and accumulate mutations
how do Papillomaviruses inactivate Rb?
has E7 that sequesters Rb allowing constitutive progression in cell cycle
-allows E2f to be constantly free and active
papillomaviruses are ___
lytic
how do papillomaviruses cause cancer
presence of a sub genomic segment of papillomavirus DNA (viral promoter E6, E7) which has accidentally integrated into the host DNA and permanently overrides the p53 genome maintenance function without cell lysis ==> cancer
where do papillomaviruses deregulate the cell cycle
at G1 (Rb) and S phase (p53)
how do simple retroviruses cause cancer
transduce or insertionally activate cellular genes that lead to cancer
how do complex retroviruses lead to cancer
trans-activate cellular genes that are both proliferative in function and repress tumor suppressors like p53
how do papillomaviruses cause cancer
E6 and E7 proteins inactivate host tumor suppressor p53 and Rb proteins
viruses provide 2-3 mutations necessary for oncogenic transformation. where do the rest come from?
over time because p53 genome maintenance function is lost and mutations accumulate
