Different rat-derived transforming retroviruses code for an immunologically related intracellular phosphoprotein.

Young, Howard A.; Shih, Thomas Y.; Scolnick, Edward M.; Rasheed, Suraiya; Gardner, Murray B.

doi:10.1073/pnas.76.7.3523

Cited by 36 publications

(34 citation statements)

References 24 publications

(13 reference statements)

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“…Thus, the p29 protein of Ra-SV appears to be a fusion protein analogous to the larger fusion proteins detected in a variety of other oncogenic retroviruses. The molecular structure of the genomic RNA of Ra-SV has not been elucidated, but rat 30S genes do not seem to be present in Ra-SV (52). This observation is consistent with our recent studies of Ha-SV, which showed that the p21-coding gene in Ha-SV is not comprised of rat 30S genetic sequences (15).…”

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confidence: 86%

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Transformation by rat-derived oncogenic retroviruses.

Scolnick¹

1981

Microbiological Reviews

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Retroviruses are reverse transcriptase-containing infectious agents which replicate through a deoxyribonucleic acid (DNA) copy of their genomic ribonucleic acid (RNA) (44). During the past decade, our understanding of the genetic structure and life cycle of retroviruses has increased rapidly due in large measure to the development of quantitative cell culture assays for retroviruses and the discovery of the enzymatic machinery involved in the viral replicative cycle. The discovery of reverse transcriptase (1, 45) removed a major intellectual barrier to our understanding of RNA tumor viruses and provided a rational approach for applying conventional techniques of molecular biology to the study of how these agents transform specific target cells.The most intriguing biological aspect of retrovirology has been the diverse array of oncogenic retroviruses that has been discovered. Most isolates of retroviruses replicate in cell cultures and animals without causing any obvious pathogenic effects. On the other hand, highly oncogenic retroviruses have been isolated from several vertebrates. Approximately 10 to 20 of these highly oncogenic variants have been isolated, and reviews have been written recently categorizing the viruses and discussing their biology and molecular structure (3,18,35,48). Each of these viruses can cause abnormal growth of various target cells in cell culture, and in some cases a good correlation exists between the pathological effects of the virus in cell culture and the oncogenicity of the virus in its susceptible vertebrate hosts.During the past 8 to 9 years, my laboratory has been studying one particular group of these highly oncogenic viruses isolated from rats. Three different isolates of highly oncogenic retroviruses have been isolated from rats. The first isolate was described in 1964 by Harvey, in the course of her studies with mouse-derived Moloney leukemia virus (Mo-MuLV) (7,20). Inoculation of Mo-MuLV into mice results in overt thymic leukemia in infected animals. In early studies, investigators routinely maintained their leukemogenic stocks by passage of these viruses from mouse to mouse. In the course of such t Review based on the Eli Lilly & Co. Award Lecture given at the 1980 American Society for Microbiology Annual Meeting. animal passage, Harvey inoculated rats with Mo-MuLV, and these animals also developed thymic leukemia. However, in the course of such rat passage of Mo-MuLV, Harvey noted that the disease syndrome changed when the rat-passaged virus was reinoculated into mice. Instead of causing thymic leukemia after a relatively long latent period, the virus induced the rapid onset of fibrosarcomas and an erythroid leukemia with splenomegaly. The etiological agent that was responsible for the new disease syndrome was named Harvey sarcoma virus (Ha-SV), and this agent was subsequently biologically cloned. In 1967, a second isolate of a highly oncogenic virus was isolated from rats. Kirsten (22, 23) inoculated another mouse leukemia-inducing virus into Wistar Furth rats and noted ...

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“…A surprising result was the observation that Ra-SV coded for a related protein, p29 (52). In this case, the src protein was a p21-like protein fused to a rat type C viral structural protein which appears to be a part of the gag precursor of rat type C viruses (H. Young, personal communication).…”

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confidence: 99%

Transformation by rat-derived oncogenic retroviruses.

Scolnick¹

1981

Microbiological Reviews

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“…Both RaSV-transformed cells and RaSV-induced fibrosarcomas in rats express a transforming protein of 29 kDa which has been designated p29 or v-Ra-Ras (56,57). An important characteristic of RaSV-induced transformation is that cells transformed with different isolates of RaSV derived from different rat tumors express the same or immunologically similar p29 proteins (57).…”

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Genetic Analysis of the Rat Leukemia Virus: Influence of Viral Sequences in Transduction of the c- ras Proto-Oncogene and Expression of Its Transforming Activity

Lee

Howard

Rasheed

1998

J Virol

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The rat leukemia virus (RaLV) is an endogenous retrovirus that is spontaneously released by Sprague-Dawley rat embryo cells. The overall structure of the RaLV genome resembles that of other simple, replication-competent retroviruses, but the sequence of the long terminal repeats (LTR) is unique and unrelated to the known retroviruses. Phylogenetically, the RaLV genome appears to be more closely related to the feline leukemia virus group of retroviruses than to the murine leukemia virus group. A remarkable feature of RaLV is that it is capable of transducing a ras proto-oncogene from rat tumor cells in the form of an acutely transforming virus, designated the Rasheed strain of the rat sarcoma virus (RaSV). With the exception of the c-ras sequence, the genomes of both RaLV and RaSV are collinear. The RaSV-encoded oncogene v-Ra-rasexpresses a fusion protein with a molecular mass of 29 kDa, and it exhibits a unique structure that has not been described previously for any known virus. The 5′ end of this gene is derived from sequences encoding RaLV matrix followed by 20 bp derived from the U5 region of the RaLV LTR (RS-U5 element) which is joined at its 3′ end to sequences derived from all six (coding and noncoding) exons of the c-ras proto-oncogene at the 3′ end. This recombinational event represents a novel mechanism among the acutely transforming viruses that have been studied.

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“…Most acutely transforming retroviruses have been isolated following infection of animals with nontransforming replication-competent retroviruses, as was the case for the Harvey and Kirsten murine sarcoma viruses. However, acutely transforming viruses have also been generated in cultured cells using various nontransforming replication-competent retroviruses (15)(16)(17)23), showing that XMRV is not unique in this regard. Interestingly, production of acutely transforming viruses was facilitated by growth of the nontransforming parental viruses in chemically transformed cells or in cultured tumor cells (16,17).…”

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Acutely Transforming Retrovirus Expressing Nras Generated from HT-1080 Fibrosarcoma Cells Infected with the Human Retrovirus XMRV

Metzger

Miller

2010

J Virol

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XMRV (xenotropic murine leukemia virus-related virus) has been associated with prostate cancer (19,20) and chronic fatigue syndrome (12), although some researchers fail to detect XMRV in other populations with these diseases (4, 8). XMRV is found integrated into human genomic DNA from prostate cancer samples, indicating that it is indeed a human retrovirus and not a laboratory contaminant (3, 9). Because of the potential role of XMRV in prostate cancer, we previously tested XMRV for transforming activity in fibroblast and epithelial cell lines. Although XMRV is a simple retrovirus that does not carry a host-derived oncogene, there is precedence for transformation by retroviral Env genes (21, 22). However, transfection of XMRV proviral DNA or viral envelope expression vectors into 208F rat fibroblasts did not result in transformation, and infection of most cell types tested with XMRV did not induce transformation (13). In contrast, infection of 208F cells with XMRV did result in rare transformed foci suggestive of oncogene activation by XMRV. Characterization of cells from three transformed foci produced by infection of 208F cells with virus from HTX cells (a pseudodiploid subclone of HT-1080 fibrosarcoma cells [18]) infected with XMRV and the LAPSN retroviral vector (included as a marker for infection) revealed that all produced XMRV and that one produced a highly active transforming virus (13).Transforming virus structure. To investigate the genesis of this transforming virus, we amplified genomic DNA from the 208F focus 3 cells, which produce the transforming virus (13), by using primers that matched both murine leukemia virus (MLV) and XMRV long terminal repeats (LTRs) (small arrows near LTRs in Fig.

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Different rat-derived transforming retroviruses code for an immunologically related intracellular phosphoprotein.

Cited by 36 publications

References 24 publications

Transformation by rat-derived oncogenic retroviruses.

Transformation by rat-derived oncogenic retroviruses.

Genetic Analysis of the Rat Leukemia Virus: Influence of Viral Sequences in Transduction of the c- ras Proto-Oncogene and Expression of Its Transforming Activity

Acutely Transforming Retrovirus Expressing Nras Generated from HT-1080 Fibrosarcoma Cells Infected with the Human Retrovirus XMRV

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