#26 oncogenic viruses Flashcards
transformation can be defined as
the introduction of a inheritable change in a cell that causes changes in growth phenotype and immortalisation (change is passed from mother to daughter)
are cancers monoclonal or clonal
cancers are clonal
meaning they are produced from a single cell that has been transformed
one cell undergoes a transformation and that cell will pass the change on to its daughters
how do transformed cells differ from normal cells?
- lack inhibition of growth
- lack dependence on exogenous growth factors
- lack anchorage dependence
- not all oncogenic viruses can transform cells in culture
what are the 5 phases of the cell cycle and what occurs in them
G0 phase - the quiescent resting phase
G1 phase - synthesis of proteins required for DNA synthesis occurs (enzymes are synthesised)
s phase: DNA synthesis occurs
G2 phase: synthesis of proteins for daughter cells occurs
M phase - mitosis occurs / cell will enter the G0 phase or go back into G1 and begin division again
what are go and stop signals required for
Go signals: growth factors, oncogenes, cyclins, CDKs
- required to make to make the switch from the G0 to the G1 phase
Stop signals
- used for control
- can inhibit go signals
where is the point of no return and how do you get there
between the G0 and restriction point the cell is paused and waiting in response to environmental signals (go signals/stop signals)
when there is enough go signal in the g1 phase the cell will reach a point of no return where the cell will not be able to turn back
it will divide - DNA synthesis will occur in s phase and so on
what are genes encoding go signals called
proto-oncogenes
or c-onc (cellular oncogenes)
how do oncogenic viruses cause cancer
they affect the expression or function of proteins that play roles in cell growth and division
what are tumor suppressor genes
they are genes encoding proteins that are involved in negative regulation of cell growth (they’re stop signals)
i.e. P53 and rb
what are the 4 classes of oncogene
give examples of each
what can viruses do to these c-onc genes
Growth factors - EGF
growth factor receptors - EGF receptor
intracellular signal transducers - Elk, raf, Mek, Ras
transcription factors - Elk-1, SRF
they all assist in cell growth and division (c-onc)
virus can mutate all of these genes
name the 6 viruses that can induce cancer
DNA
- Epstein barr virus EBV (herpesviridae)
- HPV (papovaviridae)
- human polyomavirus (papovaviridae)
- hepatitis B virus (hepadnaviridae)
RNA
- HTLV-1
- Hepatitis C (Flaviviridae)
what are the features of RNA tumor viruses
- they are a non-lytic infection
- integration is essential part of the replication cycle
- they may bring a v-onc however it will have a cellular counterpart (it uses a cellular oncogene as a viral oncogene)
- transformation involves stimulating the activators of the cell cycle (c-onc’s) - they will do this by mutating it or activating it
what are the features of the DNA tumor viruses
- often lytic infection
- integration is not an essential part of the virus cycle but may occur in transformed cells
- the v-onc’s they bring are usually unique viral gene products - they do not have a cellular counterpart. they bring their own v-onc
- transformation involves inactivation of inhibitors of the cell cycle (inhibition of tumor suppressor genes)
what are the two categories of oncogenic retroviruses divided into?
what are their features
Endogenous retrovirus
- integrated provirus
- transmitted in the germline to every cell
- will be passed from mother to her child
- the virus is usually totally silent
- only become a problem in response to stimuli such as irradiation, chemicals etc. virions will be produced
Exogenous retrovirus
- typical virus infection
- acquire the infection after birth
- virions will be produced - most will be replication competent
what are the features of a defective retrovirus - how does it work
- a defective retrovirus will encode a oncogene
- the onc will have replaced a viral gene i.e. pol gene
- therefore the virus is missing a gene segement
- the virus will be defective and will not be able to replicate on its own
- it can only replicate with a helper virus present (normal virus)
what is unique about rous sarcoma virus?
it is a retrovirus
it has picked up a oncogene, but is not defective
it is replication competent
when it picked up an oncogene it didnt replace any genes - it still has all of its genes hence can replicate
what are the 3 mechanisms in which an exogenous retrovirus can cause tumor production
how?
- transducing retroviruses
- introduce themselves into the host with a v-onc
- LTR will act as the promoter for the oncogene - cis-activating retroviruses
- dont have an oncogene
- the LTR of the virus drives the transcription of a nearby c-oncogene
- called insertional mutagenesis - trans-activating retroviruses
- contain a gene regulation protein or a gene activating RNA
- they will both act to activate a c-oncogene
how do transactivating (acute) retroviruses work?
- they induce a v-onc under LTR transcriptional control into the host genome
- the these viruses are mostly defective except for Rous sarcoma virus
- these viruses will not produce any infectious virus unless they have the help from a helper virus (normal virus)
- these viruses cause tumors in weeks
- tumors may be polyclonal as multiple cells can be infected and acquire a c-onc
describe how cis-activating (non-acute) retroviruses work
- perform insertational mutagenesis
- they do not encode a v-onc
- they insert into host near a c-onc
- the LTR from the virus drives transcription of the c-onc
Can occur in 2 ways
1. land next to a c-onc and the 5’LTR drives transcription of the virus and the 3’ LTR drives transcription of the c-onc
- long range: they land far away from the c-onc however the 3’ enhancer will drive transcription of the c-onc
how is Koala Retrovirus causing Leukaemia in koalas
- the virus is an exogenous retrovirus
- it is causing cancer via insertational mutagenesis
- where the virus inserts into the genome and the LTR drives transcription of a c-onc
how do trans-activating retroviruses work?
what is an example
- it is a virus that contains a gene regulation proteins
- HTLV-1 is a transactivating retrovirus -its exogenous
- causes ATL
- it transcribes two regulatory proteins that drive proliferation of the infected cell: Tax and Hbz
how does Tax and HBZ of HTLV-1 work?
what is this mechanism of cancer induction called?
they both act as gene regulation proteins for HTLV-1 to cause cell proliferation
- called transactivating retroviruses
- Tax: is a gene regulation protein, it binds to the LTR of the virus to up-regulate expression of Gag, pol and env but it also it activates many cellular interleukins (IL2 and IL-2R) to drive proliferation of the cell
HBZ: down-regulates the expression of Tax protein
but HBZ mRNA also drives proliferation of the cell
explain the regulation of HTLV1 expression and replication for HBZ and Tax protein
- initially most infected cells only produce HBZ mRNA and HBZ protein
- HBZ protein drives proliferation of the cell
- HBZ mRNA can cause bursts of Tax protein
- Bursts of tax will cause virion production and cell proliferation via activating cellular interleukins
- tax bursts can also be induced by cell stress, hypoxia, t-cell activation
- HBZ protein will act on tax to down-regulate it
how does Leukeamia from HTLV-1 develop
- occurs mainly through the expression of viral proteins HBZ, Hbz mRNA and Tax
- also can occur through insertional mutagenesis where virus inserts into host DNA and drives long range transcription of a c-onc
- the viral enhancer drives transcription of a c-onc
explain the features of tumor induction by DNA viruses
- DNA viruses transform cells as a consequence of their replication strategy
- they undergo lytic growth
- they require host enzymes to replicate their DNA which are produced in the S phase of the cell cycle
- it is in favour for the virus to push the cell to the s phase
- they use viral proteins to push the cell into the s phase of the cycle
- they often encode proteins that inactivate tumor suppressor proteins -they eliminate the stop signal
- the tumors need to have persistent expression of the viral oncogenes either as an episome or intergrated into the viral genome
- the virus is often the indirect cause of cancer - tumor formation is often multi-factorial
what are the two tumor supressor genes and what do they do
Rb and P53 gene
cellular genes that inhibit cell cycle
Rb protein controls the transition from G0 to G1 - it will activate and associate with ELF transcription factors to put a break on the cell cycle
P53 protein is a transcription factor that induces expression of proteins that arrest cell growth
lot of tumors have mutations in P53 gene
explain how some strains of HPV causes tumors
- DNA virus
- in benign warts the genome is kept as a circular episome. however in malignant cells the HPV genome randomly integrates into the genome resulting in the loss of the E2 gene
- E2 negatively represses the transcription of E6 and E7 proteins
- when E2 is lost E6 and E7 will be transcribed
- E6 and E7 will stop p53 and Rb proteins
- HPV targets p53 for degradation
explain how Hep.B causes cancer
- DNA virus
- usually a part of the genome will integrate into the host chromosome randomly
- when Hep. B integrates it will retain its X gene and its promoter. However it will become non-infectious (this is not advantageous for the virus)
- the X gene encodes a transactivating gene that may activate a nearby c-onc (Src tyrosine kinase) - insertional mutagenesis
- it has an indirect role in cancer as its a combination of the viral proteins and the international mutagenesis which causes cancer from HBV
How does Polyomavirus (SV40) cause cancer
- causes merkel cell cancer
- virus integrates into the host DNA and produces the large T antigen which has truncation mutations that make the T antigen defective initiating DNA replication
what cancers does EBV cause
How does EBV cause cancer
causes burkitts lymphoma, nasopharyngeal cancer, B-cell lymphomas, hodgekins lymphoma
In burkitts lymphoma the EBV cells cause cloal expansion of B-cells - enhances the chances of genetic accidents such as the chromosomal translocation of C-myc which encodes a ‘go signal’ (G1 to S signal)
Can cause the c-myc to be under transcriptional control of the Ig heavy chain enhancer which causes the overproduction of c-myc
causes production of tumors
