In-situ Demonstration of Mitogen-activated Protein Kinase Erk 1/2 Signalling Pathway in Contagious Respiratory Tumours of Sheep and Goats

Heras, M. De las; Ortı́n, A.; Benito, Alfredo A.; Summers, Christina; Ferrer, Luís Miguel; Sharp, JM

doi:10.1016/j.jcpa.2006.02.002

Cited by 36 publications

(30 citation statements)

References 31 publications

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“…OPA tumor sections were used as positive controls. The activation of MAPK Erk1/2 signaling pathway was detected in tumors induced by JS-RD and JSRV by immunohistochemistry employing rabbit polyclonal anti-phospho-Erk1/2 (Cell Signaling) as described previously (11).…”

Section: Methodsmentioning

confidence: 99%

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Expression of the Jaagsiekte Sheep Retrovirus Envelope Glycoprotein Is Sufficient To Induce Lung Tumors in Sheep

Caporale

Cousens

Centorame

et al. 2006

J Virol

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Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma (OPA). The expression of the JSRV envelope (Env) alone is sufficient to transform a variety of cell lines in vitro and induce lung cancer in immunodeficient mice. In order to determine the role of the JSRV Env in OPA tumorigenesis in sheep, we derived a JSRV replication-defective virus (JS-RD) which expresses env under the control of its own long terminal repeat (LTR). JS-RD was produced by transiently transfecting 293T cells with a two plasmid system, involving (i) a packaging plasmid, with the putative JSRV packaging signal deleted, expressing the structural and enzymatic proteins Gag, Pro, and Pol, and (ii) a plasmid which expresses env in trans for JS-RD particles and provides the genomes necessary to deliver JSRV env upon infection. During the optimization of the JS-RD system we determined that both R-U5 (in the viral 5 LTR) and the env region are important for JSRV particle production. Two independent experimental transmission studies were carried out with newborn lambs. Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma (OPA) (29). OPA is one of the most common viral diseases of sheep in many regions of the world (38) and is a unique large-animal model for lung carcinogenesis (14,26).Among oncogenic retroviruses, JSRV appears to employ unique mechanisms to induce cell transformation. The JSRV envelope glycoprotein (Env) is an oncoprotein (1, 20, 33) which induces transformation of a variety of primary and established cell lines in vitro (1, 9, 18-20, 33, 44) via the activation of the phosphatidylinositol 3-kinase/Akt and MEK/mitogen-activated protein kinase (MAPK) pathways by as-yet-uncharacterized mechanisms (18,19,27). In addition, immunodeficient mice inoculated with an adeno-associated virus vector expressing the JSRV Env develop lung adenocarcinoma, indicating that the JSRV Env can also behave as an oncoprotein in vivo, although the same vector is not efficient in inducing tumors in immunocompetent mice (41).The role of the JSRV Env in OPA tumorigenesis in sheep, the natural host of JSRV infection, is not completely clear. OPA is experimentally reproducible when lambs are inoculated intratracheally with concentrated virus preparations obtained from lung secretions (or lung fluid) of OPA-affected sheep or from supernatant of cells transfected with JSRV infectious molecular clones (12,29,35,37). The incubation period, in this experimental model of OPA, can be as short as a few weeks, suggesting that the viral Env can function as a dominant oncogene in vivo as well as in vitro. However, naturally occurring OPA is characterized by a very long incubation period lasting even a few years (6,39,40). Diseases with a long incubation time, in retrovirus-induced tumorigenesis, are often associated with the classical mechanisms of insertional activation. This is the case with, for example, mice, chickens, and cats with leukemias induced by Moloney murine leukemia virus, avian leuko...

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Section: Methodsmentioning

confidence: 99%

“…Involvement of the H/N-Ras-MEK-MAPK pathway has been shown in JSRV-induced cell transformation in vitro and in vivo (11,19). In order to test whether virus replication and spread could determine differences in MAPK (Erk1/2) activation, we performed immunohistochemistry in tissues from both JS-RD-and JSRV-inoculated animals.…”

Section: Js-rd Design and Developmentmentioning

confidence: 99%

Expression of the Jaagsiekte Sheep Retrovirus Envelope Glycoprotein Is Sufficient To Induce Lung Tumors in Sheep

Caporale

Cousens

Centorame

et al. 2006

J Virol

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“…A recent study on JSRV and ENTV tumoural tissues gives more clues to understand the JSRV complex signalling cascades. In naturally and experimentally induced OPA, MAPK Erk1/2 seems to be the predominant activated pathway [20].…”

Section: Mechanisms Of Oncogenesismentioning

confidence: 99%

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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“…Pharmacological inhibitors for H-or N-ras (farnesyl transferase inhibitor) and for MEK1/2 completely inhibited transformation of NIH-3T3 fibroblasts, and MAPK activity was increased in transformed cells [102,103]. Consistent with this, immunohistochemical staining of tumour tissues from naturally and experimentally induced OPA revealed strong activation of Raf, MEK and MAPK [102,112,117]. p38 MAPK, which plays a crucial role in the regulation of apoptosis, cell cycle progression and cell proliferation, also was found to be constitutively activated in transformed cells [102,103].…”

Section: Jaagsiekte Sheep Retrovirus (Jsrv)mentioning

confidence: 53%

Oncogenesis by retroviruses: old and new paradigms

Maeda

Fan

Yoshikai

2008

Reviews in Medical Virology

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Retroviruses are associated with a variety of diseases including an array of malignancies, immunodeficiencies and neurological disorders. In particular, studies of oncogenic retroviruses established fundamental principles of modern molecular cancer biology. Studies of avian Rous sarcoma virus (RSV) led to the discovery of the viral oncogene src, and this was followed by the discovery of other viral oncogenes in retroviruses of mammals including rodents, cats, monkeys and so forth. Studies of the viral oncogenes in turn led to the discovery of cellular proto-oncogenes in the host genome; cellular oncogenes have been shown to be activated in a variety of human cancers, including those with no viral involvement. Oncogenic animal retroviruses can be divided into two groups based on their mechanisms of tumourigenesis, acute transforming retroviruses and nonacute retroviruses. Acute transforming retroviruses are typically replication defective and they induce tumours rapidly due to expression of their viral oncogenes. Nonacute retroviruses are replication competent and they induce tumours with longer latencies, by activating cellular proto-oncogenes in the tumour cells; this results from insertion of proviral DNA in the vicinity of the activated proto-oncogene. More recently, human T-cell leukaemia virus type I (HTLV-I) was discovered as an etiological agent of human cancer (adult T-cell leukaemia [ATL]); this virus also encodes regulatory genes some of which are important for its oncogenic potential. Most recently, the retroviral structural protein Envelope (Env) has been shown to be directly involved in oncogenic transformation for certain retroviruses. Env-induced transformation is a new paradigm for retroviral oncogenesis. In this review, we will summarise research on retrovirus oncogenic transformation over the past 100 years since the first published report of an oncogenic virus with particular attention to Env-induced transformation.

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In-situ Demonstration of Mitogen-activated Protein Kinase Erk 1/2 Signalling Pathway in Contagious Respiratory Tumours of Sheep and Goats

Cited by 36 publications

References 31 publications

Expression of the Jaagsiekte Sheep Retrovirus Envelope Glycoprotein Is Sufficient To Induce Lung Tumors in Sheep

Expression of the Jaagsiekte Sheep Retrovirus Envelope Glycoprotein Is Sufficient To Induce Lung Tumors in Sheep

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

Oncogenesis by retroviruses: old and new paradigms

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