Mutational Analysis of the Cytoplasmic Tail of Jaagsiekte Sheep Retrovirus Envelope Protein

Hull, Stacey; Fan, Hung

doi:10.1128/jvi.00013-06

Cited by 42 publications

(55 citation statements)

References 26 publications

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“…Based on transformed morphology, the transformation observed by Liu and Miller was higher than that observed in this study, which employed HA-tagged Env. JSRV Env proteins containing C-terminal epitope tags have a lower efficiency of transformation than does wild-type Env (17,27,28).…”

Section: Resultsmentioning

confidence: 99%

Jaagsiekte Sheep Retrovirus Transformation in Madin-Darby Canine Kidney Epithelial Cell Three-Dimensional Culture

Johnson

Sanders

Fan

2010

J Virol

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Lung cancer is the leading cause of cancer deaths worldwide. While most cases are associated with cigarette smoking, 15% of cases in men and 53% in women occur in nonsmokers (39). Lung cancer in nonsmokers is most commonly diagnosed as adenocarcinoma (21). Jaagsiekte sheep retrovirus (JSRV) is the etiological agent of a contagious neoplasm in sheep termed ovine pulmonary adenocarcinoma (OPA) (35). OPA is derived from secretory epithelial cells, type II pneumocytes, and Clara cells and closely resembles bronchioloalveolar carcinoma (BAC) in humans (36,41). The similarities between OPA and BAC make JSRV and OPA a useful animal model for studying lung carcinogenesis.JSRV is unique because the envelope protein (Env, encoded by the env gene) is the oncogene. Expression of Env can transform cells in culture (2, 30, 43) as well as induce tumors in animals (38, 51). Initial studies illustrated the importance of the phosphatidylinositol 3-kinase (PI3K)-Akt-mTOR pathway in JSRV Env transformation. It is now clear that there are PI3K-dependent and -independent mechanisms of Akt-mTOR signaling. PI3K-dependent signaling was evident because JSRV Env-transformed cell lines have constitutively active Akt and inhibiting PI3K prevented transformation and caused reversion of the transformed phenotype (24,25,37,52). On the other hand, PI3K-independent Akt activation was later demonstrated, since cells in which PI3K was disabled could still be transformed by JSRV and, under these conditions, there was still activation of Akt (29).More recently, the H/N-Ras-MEK-mitogen-activated protein kinase (MAPK) pathway was found to play a more important role in JSRV Env transformation, since inhibiting MEK1 and H/N-Ras prevented transformation in NIH 3T3 and RK3E cell monolayers (28). Note that p38 MAPK has a negative role in JSRV Env transformation, as inhibiting p38 MAPK increases transformation. The finding that JSRV Env does not induce transformation solely through the PI3K-Akt-mTOR pathway is supported by the fact that not all OPA tissues demonstrate activated Akt (46). Together, these results underscore the complexity of JSRV Env transformation and the need to further understand the signaling pathways involved in transformation.Madin-Darby canine kidney (MDCK) epithelial cells grown in three-dimensional (3-D) culture by being embedded in Engelbreth-Holm-Swarm tumor extract (Matrigel) or collagen readily form spherical structures termed "acini." Acini grow as a single layer of polarized cells that are attached to the underlying basement membrane and enclose a central hollow lumen (7,26,33,34). Acinar structure and cell-cell and cell-environment interactions mimic what occurs in vivo. Maintenance of this highly ordered structure is critical for proper differentiated cell function, and when it is disrupted, malignancy can ensue. The events of MDCK acinus formation have been well defined and include cell polarization, secretion of basement membrane, formation of tight junctions, and responsiveness to apoptotic and proliferative suppressive si...

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Section: Resultsmentioning

confidence: 99%

Jaagsiekte Sheep Retrovirus Transformation in Madin-Darby Canine Kidney Epithelial Cell Three-Dimensional Culture

Johnson

Sanders

Fan

2010

J Virol

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“…Mutations of the YXXM motif of the JSRV-env gene abolish cell transformation of NIH-3T3 [43,61] and rat 208F and RK3E cells [38]. Akt activation was observed in different cell lines transformed by JSRV (Fig.…”

Section: Mechanisms Of Oncogenesismentioning

confidence: 88%

“…Activation of this signalling cascade leads to translocation of MAPK into the nucleus, where they activate different transcription factors. The Ras-MEK-MAPK pathway is activated in JSRVtransformed NIH 3T3 and RK3E cells [38,46] (Fig. 3).…”

Section: Mechanisms Of Oncogenesismentioning

confidence: 96%

“…Deletion experiments show that the TM (transmembrane) region of the envelope is the main determinant for cell transformation [12,36,38]. In addition to the TM region, deletions of the SU (surface) glycoprotein (going from the signal peptide to the junction between the SU and TM subunits) also abolish transformation induced by the envelope, suggesting that multiple domains of SU may be involved in cellular transformation.…”

Section: Mechanisms Of Oncogenesismentioning

confidence: 99%

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Jaagsiekte Sheep Retrovirus (JSRV): from virus to lung cancer in sheep

et al. 2007

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-Jaagsiekte Sheep Retrovirus (JSRV) is a betaretrovirus infecting sheep. This virus is responsible for a pulmonary adenocarcinoma, by transformation of epithelial cells from the bronchioli and alveoli. This animal cancer is similar to human bronchioloalveolar cancer (BAC), a specific form of human lung cancer for which a viral aetiology has not yet been identified. JSRV interacts with target cells through the membrane receptor Hyal2. The JSRV genome is simple and contains no recognised oncogene. It is now well established that the viral envelope protein is oncogenic by itself, via the cytoplasmic domain of the transmembrane glycoprotein and some domains of the surface glycoprotein. Activation of the PI3K/Akt and MAPK pathways participates in the envelopeinduced transformation. Tumour development is associated with telomerase activation. This review will focus on the induction of cancer by JSRV.

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“…Results from the previous experiment suggested that the LTRs are not entirely responsible for the cell-type-specific oncogenicity observed in naturally infected sheep and that perhaps other regions of the ovine betaretroviral genome contribute to the disease spectrum. The genomic sequences of JSRV and ENTV differ at the 3Ј end of the env gene, just upstream of the 3Ј LTR (29), in a region that has been shown to be dispensable for transformation (17), but possesses enhancer functions in other retroviruses (3,18). To test the potential role of this region in determining disease tropism, we incorporated the ϳ75-bp sequence upstream of the JSRV and ENTV-1 3Ј LTRs into AJAP and AE 1 AP to create A JE JAP and A EE E 1 AP, where JE stands for JSRV element and EE stands for ENTV element (Fig.…”

Section: Resultsmentioning

confidence: 99%

Jaagsiekte Sheep Retrovirus and Enzootic Nasal Tumor Virus Promoters Drive Gene Expression in All Airway Epithelial Cells of Mice but Only Induce Tumors in the Alveolar Region of the Lungs

Linnerth-Petrik

Halbert

et al. 2011

J Virol

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Jaagsiekte sheep retrovirus (JSRV) induces tumors in the distal airways of sheep and goats, while the closely related enzootic nasal tumor virus type 1 (ENTV-1) and ENTV-2 induce tumors in the nasal epithelium of sheep and goats, respectively. When expressed using a strong Rous sarcoma virus promoter, the envelope proteins of these viruses induce tumors in the respiratory tract of mice, but only in the distal airway. To examine the role of the retroviral long terminal repeat (LTR) promoters in determining tissue tropism, adeno-associated virus (AAV) vectors expressing alkaline phosphatase under the control of the JSRV, ENTV-1, or ENTV-2 LTRs were generated and administered to mice. The JSRV LTR was active in all airway epithelial cells, while the ENTV LTRs were active in the nasal epithelium and alveolar type II cells but poorly active in tracheal and bronchial epithelial cells. When vectors were administered systemically, the ENTV-1 and -2 LTRs were inactive in major organs examined, whereas the JSRV showed high-level activity in the liver. When a putative transcriptional enhancer from the 3 end of the env gene was inserted upstream of the JSRV and ENTV-1 LTRs in the AAV vectors, a dramatic increase in transgene expression was observed. However, intranasal administration of AAV vectors containing any combination of ENTV or JSRV LTRs and Env proteins induced tumors only in the lower airway. Our results indicate that mice do not provide an adequate model for nasal tumor induction by ENTV despite our ability to express genes in the nasal epithelium.Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) are closely related oncogenic betaretroviruses that infect sheep and goats. These viruses share greater than 90% sequence identity and utilize the same cellular receptor for virus attachment and entry (10, 32), yet they cause distinctly different diseases. JSRV transforms secretory epithelial cells of the distal lung leading to ovine pulmonary adenocarcinoma (OPA) (28,34). ENTV also transforms secretory epithelial cells, although in this case the target cells are located in the nasal mucosa and lead to the formation of a neoplastic disease called enzootic nasal adenocarcinoma (ENA) (9). Two distinct viruses have been implicated in the etiology of ENA, one in sheep (ENTV-1) and one in goats (ENTV-2), and the genomic sequences of both have been determined (7,26,38).It is currently not known how such different diseases result from infection by these closely related retroviruses. Experimental induction of OPA in sheep has been demonstrated using a molecular clone of JSRV (30); however, the lack of a cell culture system capable of propagating ENTV, the fact that an infectious molecular clone of ENTV has not yet been published, and the limitation that experiments using sheep are expensive, have made it difficult to study the mechanism of disease tropism in sheep. Therefore, we developed a model to study JSRV and ENTV tumorigenesis in mice using adenoassociated virus (AAV) vectors (41). AAV vectors made w...

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Mutational Analysis of the Cytoplasmic Tail of Jaagsiekte Sheep Retrovirus Envelope Protein

Cited by 42 publications

References 26 publications

Jaagsiekte Sheep Retrovirus Transformation in Madin-Darby Canine Kidney Epithelial Cell Three-Dimensional Culture

Jaagsiekte Sheep Retrovirus Transformation in Madin-Darby Canine Kidney Epithelial Cell Three-Dimensional Culture

Jaagsiekte Sheep Retrovirus (JSRV): from virus to lung cancer in sheep

Jaagsiekte Sheep Retrovirus and Enzootic Nasal Tumor Virus Promoters Drive Gene Expression in All Airway Epithelial Cells of Mice but Only Induce Tumors in the Alveolar Region of the Lungs

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