View source for Biology:Rous sarcoma virus

{{Short description|Species of virus}}
{{virusbox
| parent = Alpharetrovirus
| species = Rous sarcoma virus
}}

'''Rous sarcoma virus''' ('''RSV''') ({{IPAc-en|r|aʊ|s}}) is a [[Biology:Retrovirus|retrovirus]] and is the first [[Biology:Oncovirus|oncovirus]] to have been described. It causes [[Medicine:Sarcoma|sarcoma]] in chickens.

As with all retroviruses, it reverse transcribes its RNA genome into cDNA before integration into the host DNA.

==History==
RSV was discovered in 1911 by Peyton Rous, working at Rockefeller University in New York City, by injecting cell free extract of [[Biology:Chicken|chicken]] tumour into healthy Plymouth Rock chickens. The extract was found to induce oncogenesis. The tumour was found to be composed of connective tissue (a [[Medicine:Sarcoma|sarcoma]]).<ref name="pmid19867354">{{cite journal | author = Rous P | title = A Transmissible Avian Neoplasm (Sarcoma of the Common Fowl) | journal = J. Exp. Med. | volume = 12 | issue = 5 | pages = 696–705 |date=September 1910 | pmid = 19867354 | pmc = 2124810 | doi = 10.1084/jem.12.5.696}}</ref><ref name="pmid19867421">{{cite journal | author = Rous P | title = A Sarcoma of the Fowl Transmissible by an Agent Separable from the Tumor Cells | journal = J. Exp. Med. | volume = 13 | issue = 4 | pages = 397–411 |date=April 1911 | pmid = 19867421 | pmc = 2124874 | doi =10.1084/jem.13.4.397 }}</ref> Thus, RSV became known as the first oncogenic retrovirus that could be used to study the development of cancer molecularly.<ref name="pmid22110182">{{cite journal |vauthors=Weiss RA, Vogt PK | title = 100 years of Rous sarcoma virus | journal = J. Exp. Med. | volume = 208 | issue = 12 | pages = 2351–5 |date=November 2011 | pmid = 22110182 | pmc = 3256973 | doi = 10.1084/jem.20112160 }}</ref>

In 1958, Harry Rubin and [[Biography:Howard Martin Temin|Howard Temin]] developed an assay where chicken embryo fibroblasts could be altered morphologically by RSV infection. Two years later Temin concluded that the transformed morphology of the cells was controlled by a genetic property of RSV. At that time it was unknown, but later the ''src'' gene was identified as responsible for morphological transformation in healthy cells. During the 1960s, two findings emerged: replication-competent isolated viruses were related to RSV, but were non-transforming, and an isolated replication-defective strain of RSV was transformation-competent. These two findings gave rise to the notion that viral replication and malignant transformation are separate processes in RSV.<ref name="pmid11389470">{{cite journal | author = Martin GS | title = The hunting of the Src | journal = Nat. Rev. Mol. Cell Biol. | volume = 2 | issue = 6 | pages = 467–75 |date=June 2001 | pmid = 11389470 | doi = 10.1038/35073094 | s2cid = 205016442 }}</ref>

Rous was awarded the Nobel Prize in Physiology or Medicine for the significance of his discovery in 1966.<ref>Nobelprize.org ''[https://www.nobelprize.org/nobel_prizes/medicine/laureates/1966/rous.html The Nobel Prize in Physiology or Medicine 1966: Peyton Rous]'', retrieved 1 Jul 2012</ref> Subsequently, other oncogenic human viruses, such as [[Biology:Epstein–Barr virus|Epstein–Barr virus]], were discovered. Furthermore, oncogenes were found initially in retroviruses and then in cells.<ref name="pmid22110182" />

==Structure and genome==
{{Infobox rfam
| Name = Retroviral 3'UTR stability element
| image = RF01417.png
| width = 200
| caption = Predicted secondary structure of the Rous sarcoma virus retroviral 3'UTR stability element
| Symbol =
| AltSymbols =
| Rfam = RF01417
| miRBase =
| miRBase_family =
| RNA_type = Cis-reg
| Tax_domain =
| CAS_number =
| EntrezGene =
| HGNCid =
| OMIM =
| PDB =
| RefSeq =
| Chromosome =
| Arm =
| Band =
| LocusSupplementaryData =
}}
RSV is a class VI enveloped virus with a positive sense RNA genome having a DNA intermediate.

Freely replicating RSV strains such as Prague-C have four genes:<ref>{{cite web |title=Rous sarcoma virus - Prague C, complete genome |url=https://www.ncbi.nlm.nih.gov/nuccore/J02342.1 |date=26 July 2016}}</ref>
* gag – encodes capsid proteins
* pol – encodes reverse transcriptase
* env – encodes the envelope gene
* [[Biology:V-Src|src]] – encodes a [[Biology:Tyrosine kinase|tyrosine kinase]] that attaches phosphate groups to the amino acid [[Chemistry:Tyrosine|tyrosine]] in host cell proteins.

However, not all RSV strains have all four genes that allow it to both replicate on its own and cause transformation. It is not at all clear whether Rous's original strain was able to replicate on its own or if some descendants acquired this ability later.<ref name=p7931166>{{cite journal |last1=Yatsula |first1=B. A. |last2=Geryk |first2=J. |last3=Briestanska |first3=J. |last4=Karakoz |first4=I. |last5=Svoboda |first5=J. |last6=Rynditch |first6=A. V. |last7=Calothy |first7=G. |last8=Dezelee |first8=P. |title=Origin and evolution of the c-src-transducing avian sarcoma virus PR2257 |journal=Journal of General Virology |date=1 October 1994 |volume=75 |issue=10 |pages=2777–2781 |doi=10.1099/0022-1317-75-10-2777 |doi-access=free |pmid=7931166|quote=The replication competent strains of Rous sarcoma virus (RSV) are exceptional in that they contain a complete set of replicative genes in addition to the transduced oncogene sequences. In this respect, they differ markedly from all other acutely transforming retroviruses, in which a large part of the replicative genes have been lost during transduction of cellular proto-oncogenes. However, since both the Bryan strain of RSV (Lerner & Hanafusa, 1984) and RSV29 (Dutta et al., 1985), the closest isolate to the original Rous tumour virus, lack the env gene, it is likely that the ancestral virus was also replication defective.}} &ndash; See Vogt PK (2019) for discussion of whether PR2257 constitutes a ''de novo'' uptake.</ref> Very few acutely oncogenic or transforming retroviruses are capable of replication without a helper virus, making non-defective strains of RSV quite unique.<ref>{{cite journal |last1=Vogt |first1=PK |title=The Importance of Being Non-Defective: A Mini Review Dedicated to the Memory of Jan Svoboda. |journal=Viruses |date=18 January 2019 |volume=11 |issue=1 |page=80 |doi=10.3390/v11010080 |pmid=30669277|doi-access=free|pmc=6360021 }}</ref>

The RSV genome has terminal repeats enabling its integration into the host genome and also overexpression of RSV genes.

===Src gene===
{{main|Biology:V-Src}}
The src gene is [[Biology:Oncogene|oncogenic]] as it triggers uncontrolled growth in abnormal host cells. It was the first retroviral oncogene to be discovered.<ref name="pmid22898541">{{cite journal | author = Vogt PK | title = Retroviral oncogenes: a historical primer | journal = Nat. Rev. Cancer | volume = 12 | issue = 9 | pages = 639–48 |date=September 2012 | pmid = 22898541 | pmc = 3428493 | doi = 10.1038/nrc3320 }}</ref> It is an acquired gene, found to be present throughout the [[Biology:Animal|animal kingdom]] with high levels of conservation between species.

The chicken src gene was taken up by RSV and incorporated into its [[Biology:Genome|genome]].<ref>{{cite journal |last1=Swanstrom |first1=R |last2=Parker |first2=R C |last3=Varmus |first3=H E |last4=Bishop |first4=J M |title=Transduction of a cellular oncogene: the genesis of Rous sarcoma virus. |journal=Proceedings of the National Academy of Sciences |date=May 1983 |volume=80 |issue=9 |pages=2519–2523 |doi=10.1073/pnas.80.9.2519 |pmid=6302692 |doi-access=free|pmc=393857 |bibcode=1983PNAS...80.2519S }}</ref>

The v-Src gene is thought to confer the virus with the advantage of being able to stimulate uncontrolled [[Biology:Mitosis|mitosis]] of host cells, providing abundant cells for fresh [[Medicine:Infection|infection]].<ref>{{cite journal |last1=Wyke |first1=AW |last2=Frame |first2=MC |last3=Gillespie |first3=DA |last4=Chudleigh |first4=A |last5=Wyke |first5=JA |title=Mitogenesis by v-Src: fluctuations throughout G1 of classical immediate early AP-1 and mitogen-activated protein kinase responses that parallel the need for the oncoprotein. |journal=Cell Growth & Differentiation |date=October 1995 |volume=6 |issue=10 |pages=1225–34 |pmid=8845299}}</ref> The src gene is not essential for RSV reproduction but it greatly increases [[Biology:Virulence|virulence]] when present.<ref name="pmid22898541"/>

Src is a tyrosine kinase involved in regulation of cell growth and differentiation. It has an SH2 and SH3 domain, which are responsible for its activation and deactivation.<ref name="pmid11389470" />

===RNA secondary structure===
The RNA genome of RSV contains an extremely long [[Biology:Three prime untranslated region|3' UTR]] that ranges between 5–7 kb in length which would usually direct it toward nonsense mediated decay (NMD) within the eukaryotic host cell.  A conserved [[Biology:Secondary structure|secondary structure]] element has been identified within the 3'UTR and is known as the Rous Sarcoma Virus Stability Element (RSE).<ref name="pmid16301601">{{cite journal |vauthors=Weil JE, Beemon KL | title = A 3' UTR sequence stabilizes termination codons in the unspliced RNA of Rous sarcoma virus | journal = RNA | volume = 12 | issue = 1 | pages = 102–10 |date=January 2006 | pmid = 16301601 | pmc = 1370890 | doi = 10.1261/rna.2129806 }}</ref> This element has been shown to prevent the degradation of the [[Biology:RNA splicing|unspliced]] viral RNA.<ref name="pmid16301601"/>

The RSE element was first identified in the genome of the Rous Sarcoma Virus but appears to be widely conserved across the avian retrovirus family. The RSE element is ~300 bp in length and located downstream of the gag natural translational termination codon. The secondary structure of the RSE element has been determined by  RNAse digestion and [[Biology:Nucleic acid structure determination#SHAPE|SHAPE chemistry]] analysis.<ref name="pmid19091866">{{cite journal |vauthors=Weil JE, Hadjithomas M, Beemon KL | title = Structural characterization of the Rous sarcoma virus RNA stability element | journal = J. Virol. | volume = 83 | issue = 5 | pages = 2119–29 |date=March 2009 | pmid = 19091866 | pmc = 2643715 | doi = 10.1128/JVI.02113-08 }}</ref>

Other elements that have been identified in RSV include a primer binding site.<ref name="pmid15153244">{{cite journal |vauthors=Johnson M, Morris S, Chen A, Stavnezer E, Leis J | title = Selection of functional mutations in the U5-IR stem and loop regions of the Rous sarcoma virus genome | journal = BMC Biol. | volume = 2| pages = 8 | year = 2004 | pmid = 15153244 | pmc = 428589 | doi = 10.1186/1741-7007-2-8 | doi-access = free }}</ref>

===Gag protein===
Gag proteins are necessary for virion assembly and mature virus infection of the host cell. The gag protein (Pr76) for RSV contains 701 amino acids. It is cleaved by virus encoded protease, releasing products found in the infectious virion.  These cleaved products include the matrix (MA), capsid (CA), and nucleocapsid (NC), which are able to enter other pathways to infect new cells.<ref name="pmid8083996">{{cite journal |vauthors=Wills JW, Cameron CE, Wilson CB, Xiang Y, Bennett RP, Leis J | title = An assembly domain of the Rous sarcoma virus Gag protein required late in budding | journal = J. Virol. | volume = 68 | issue = 10 | pages = 6605–18 |date=October 1994 | doi = 10.1128/JVI.68.10.6605-6618.1994 | pmid = 8083996 | pmc = 237081 }}</ref><ref name="pmid23325682">{{cite journal |vauthors=Nadaraia-Hoke S, Bann DV, Lochmann TL, Gudleski-O'Regan N, Parent LJ | title = Alterations in the MA and NC domains modulate phosphoinositide-dependent plasma membrane localization of the Rous sarcoma virus Gag protein | journal = J. Virol. | volume = 87 | issue = 6 | pages = 3609–15 |date=March 2013 | pmid = 23325682 | doi = 10.1128/JVI.03059-12 | pmc = 3592118 }}</ref>

===RSV envelope===
RSV has an envelope which has one [[Chemistry:Glycoprotein|glycoprotein]]: env. Env is made up of gp85 and gp37, which are glycoproteins that assemble into oligomers. The function of env is to bind RSV to the host cell receptor and induce fusion with the target cell in a pH independent manner. The envelope is acquired during [[Biology:Exocytosis|exocytosis]].  The virus buds or pushes on the plasma membrane, which allows it to leave the cell with a new outer membrane from the host cell.<ref name="pmid8083996" /><ref name="pmid2847170">{{cite journal |vauthors=Einfeld D, Hunter E | title = Oligomeric structure of a prototype retrovirus glycoprotein | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 85 | issue = 22 | pages = 8688–92 |date=November 1988 | pmid = 2847170 | pmc = 282525 | doi =10.1073/pnas.85.22.8688 | bibcode = 1988PNAS...85.8688E | doi-access = free }}</ref>

==Replication cycle==

===Cell entry===
There are two ways viruses can enter the host cell: cell receptor [[Biology:Endocytosis|endocytosis]] or fusion. Fusion occurs when the virus fuses together with the target cell membrane and releases its genome into the cell. RSV enters the host cell through fusion of the host cell membrane.<ref name="pmid2168989">{{cite journal |vauthors=Gilbert JM, Mason D, White JM | title = Fusion of Rous sarcoma virus with host cells does not require exposure to low pH | journal = J. Virol. | volume = 64 | issue = 10 | pages = 5106–13 |date=October 1990 | doi = 10.1128/JVI.64.10.5106-5113.1990 | pmid = 2168989 | pmc = 248002 }}</ref>

===Transcription===
In order for the RSV genome transcription to occur, a primer is required.  4S RNA is the primer for RSV and 70S RNA serves as the template for DNA synthesis. Reverse transcriptase, an RNA-dependent DNA polymerase, transcribes viral RNA into the full length DNA complement.<ref name="pmid4132919">{{cite journal | vauthors = Dahlberg JE, Sawyer RC, Taylor JM, Faras AJ, Levinson WE, Goodman HM, Bishop JM | title = Transcription of DNA from the 70S RNA of Rous sarcoma virus. I. Identification of a specific 4S RNA which serves as primer | journal = J. Virol. | volume = 13 | issue = 5 | pages = 1126–33 | date = May 1974 | doi = 10.1128/JVI.13.5.1126-1133.1974 | pmid = 4132919 | pmc = 355423 }}</ref>

==References==
{{Reflist|35em}}

==External links==
* [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/R/RSV.html the Rous sarcoma virus (RSV) at rcn.com] {{Webarchive|url=https://web.archive.org/web/20060429060241/http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/R/RSV.html |date=2006-04-29 }}
* [http://micro.magnet.fsu.edu/primer/techniques/fluorescence/gallery/cells/cv1/cv1cells.html molecular expressions at magnet.fsu.edu] {{Webarchive|url=https://web.archive.org/web/20060213055803/http://micro.magnet.fsu.edu/primer/techniques/fluorescence/gallery/cells/cv1/cv1cells.html |date=2006-02-13 }}
* {{MeshName|Rous+sarcoma+virus}}
* [http://rfam.org/family/RF01417 Rfam entry for retroviral 3'UTR stability element]

{{Retroviruses}}
{{Taxonbar|from=Q1444330}}

{{DEFAULTSORT:Rous Sarcoma Virus}}
[[Category:Alpharetroviruses]]

{{Sourceattribution|Rous sarcoma virus}}