ENVB 437 Lecture Notes - Lecture 11: Avian Sarcoma Leukosis Virus, Interleukin 3, Human T-Lymphotropic Virus
4 Jun 2018
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Eukaryotic cells and viruses – lecture 11 (February 12th, 2018)
Slide 143 – mechanisms of cell transformation
1) Retroviral transduction of oncogene (transducing retrovirus)
2) Oncogene activation by retroviral insertion (cis-acting / nontransducing retrovirus)
3) Oncogenesis mediated by essential retrovirus proteins (trans-activating / nontransducing long-latency retrovirus)
- Acting via a different mechanism than the first 2
Slide 144 – transducing retrociruses
- Viral acquisition of cellular proto-oncogene with capacity to transform if deregulated, usually replacing viral
coding sequences (exception is RSV= src oncogene)
o Confers a replicative advantage to the virus to increase cell division
- Overexpression versus structural change in v-onc
mos vs src
- Becomes replication defective 2 o loss of viral
coding information; requires helper virus
o Can dysregulate the cell cycle
Slide 145 – mechanism of acquisition of cellular sequences
Model for retroviral transduction of a cellular proto-oncogene (cONC) to
form an acute transforming virus. A provirus is integrated upstream of a
cONC,; the insertion may increase the level of transcription of the
oncogene. Either a viral oncogene readthrough transcript is made (A) or
the provirus and the cONC gene are fused by a deletion (B) Either event
gives rise to a hybrid RNA transcript initiating in the 5’ LTR of the
provirus and extending into the oncogene. Additional proviruses
integrated elsewhere in the cellular genome can provide helper function,
forming virion particles (C) that contain both helper and hybrid RNAs.
Recombination between these two RNAs during the process of reverse
transcription (D) joins the ends of the viral genome to the hybrid RNA.
Either one or two crossovers are required depending on the structure of the
starting RNA. Reverse transcription gives rise to a fully transmissible
retroviral genome carrying the oncogene. Subsequent transmission of the
new genome (E) from doubly infected cells can occur at high efficiency
without further rearrangements.
- Heterochomatin
o The DNA becomes condensed and silenced
- Euchromatin
o Loosely arranged, ready to be transcribed
o This is where retroviruses insert, because it is loose and open
o Also because this is the area that will be likely translated by the cell
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- We can insert upstream and increase the transcription
- We need a helper virus that can provide the essential proteins during the replication
o You deleted gag and the envelope and polymerase
▪ So you have the proteins coming from the other virus in order to have all the essential proteins
for replication
▪ You then have a virus containing both the old virus stuff and the new helper virus proteins
o Cell is co-transfected with two viruses
▪ Ex: an AAV requires and adenovirus or herpesvirus in order to reproduce
Slide 146
- External signal molecules or growth factors (receptor ligands) (sis)
o These are RARE
- Cellular receptors (erbB, fms, kit)
- Second messengers in signaling cascade (kinases: src, abl, fgr, yes; mos raf)
- Transcription factors (jun, fos, myc, myb, ets, rel)
Slide 147 – structural change in acquired c-Onc
- EGF receptor
o External domain
o A transmembrane region
o Internal domain
- When a GF binds to the external domain, it activated a signalling cascade to tell the cell to do something
- In the modified receptor (gag on the outside):
o The ECD will not be able to bind EGF if it is not there, so it is not regulated and the cell proceeds cell
signalling because it is perpetually activated
▪ This causes too much cell division and possible transformation
Slide 148
- “Single hit” carcinogenesis (one event)
- Polyclonal: tumor growth initiated in every infected cell
o More than one cell lineage that is contributing to tumors throughout the body
- Tumors form within days
- Characteristic of animal retroviruses
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Eukaryotic cells and viruses lecture 11 (february 12th, 2018) Slide 143 mechanisms of cell transformation: retroviral transduction of oncogene (transducing retrovirus, oncogene activation by retroviral insertion (cis-acting / nontransducing retrovirus, oncogenesis mediated by essential retrovirus proteins (trans-activating / nontransducing long-latency retrovirus) Acting via a different mechanism than the first 2. Viral acquisition of cellular proto-oncogene with capacity to transform if deregulated, usually replacing viral coding sequences (exception is rsv= src oncogene: confers a replicative advantage to the virus to increase cell division. Overexpression versus structural change in v-onc mos vs src. Becomes replication defective 2 o loss of viral coding information; requires helper virus: can dysregulate the cell cycle. Slide 145 mechanism of acquisition of cellular sequences. Model for retroviral transduction of a cellular proto-oncogene (conc) to form an acute transforming virus. A provirus is integrated upstream of a conc,; the insertion may increase the level of transcription of the oncogene.
