Direct transformation of rodent fibroblasts by jaagsiekte sheep retrovirus DNA

Maeda, Naoyuki; Palmarini, Massimo; Murgia, Claudio; Fan, Hung

doi:10.1073/pnas.071547598

Cited by 143 publications

(149 citation statements)

References 26 publications

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“…The first of the papers used screening of Stanford G3 panel of whole human genome radiation hybrids to identify the cellular receptor as the sheep homolog of human HYAL2 (3), a protein encoded by a gene contained within a deletion found in a significant proportion of human lung cancer (8,9). The second report used immortalized rodent cell lines to demonstrate that Env is the transforming gene of JSRV (2). Similar results have been obtained by using an immortalized chicken fibroblast cell line (J. C. DeMartini, personal communication).…”

supporting

confidence: 64%

“…Nonetheless, only one retrovirus, human T cell lymphotrophic virus (HTLV), is oncogenic in humans, and, as we enter the 21 st century, retroviral oncogenesis models may seem to be of largely historical interest. However, analyses of jaagsiekte sheep retrovirus (JSRV) by Maeda et al (2) and Rai et al (3) in this issue of PNAS reveal that oncogenic retroviruses still hold important secrets that may be directly relevant to human cancer.…”

mentioning

confidence: 99%

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New transformation tricks from a barnyard retrovirus: Implications for human lung cancer

Rosenberg

2001

Proc. Natl. Acad. Sci. U.S.A.

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supporting

confidence: 64%

mentioning

confidence: 99%

New transformation tricks from a barnyard retrovirus: Implications for human lung cancer

Rosenberg

2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Although Hyal-2 is not expressed in normal adult brains (16,36), its expression was detected from several primary human brain tumor specimens (35). Hyal-2 is a cell surface receptor for some retroviruses, the envelope protein of which mediates oncogenic transformation (18,37). In highly invasive breast cancer cell lines, preferentially expressing hyaluronan synthase 2 and Hyal-2, both synthesis and degradation of HA are up-regulated (27).…”

Section: Discussionmentioning

confidence: 99%

CD44-dependent Intracellular and Extracellular Catabolism of Hyaluronic Acid by Hyaluronidase-1 and -2

Harada¹,

Takahashi²

2007

Journal of Biological Chemistry

287

267

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Hyaluronic acid (HA) is a high molecular weight glycosaminoglycan involved in a wide variety of cellular functions. However, its turnover in living cells remains largely unknown. In this study, CD44, a receptor for HA, and hyaluronidase-1, -2, and -3 (Hyal-1, -2 and -3) were stably expressed in HEK 293 cells and the mechanism of HA catabolism was systematically investigated using fluorescein-labeled HA. CD44 was essential for HA degradation by both endogenous and exogenously expressed hyaluronidases. Hyal-1 was not able to cleave HA in living cells in the absence of CD44. Intracellular HA degradation was predominantly mediated by Hyal-1 after incorporation of HA by CD44. Although Hyal-1 was active only in intracellular space in vivo, a certain amount of the enzyme was secreted to extracellular space. This extracellular Hyal-1 was found to be incorporated by cells and such uptake of Hyal-1 was, in part, involved in the intracellular degradation of HA. Hyal-2 was involved in the extracellular degradation of HA. Hyal-2 activity was also dependent on the expression of CD44 in both living cells and enzyme assays. Immunofluorescent microscopy demonstrated that both Hyal-2 and CD44 are present on the cell surface. Without CD44 expression, Hyal-2 existed in a granular pattern, and did not show hyaluronidase activity, suggesting that localization change could contribute to Hyal-2 function. A convenient and quantitative enzyme assay was established for the measurement of Hyal-2 activity. Hyal-2 activity was detected in the membrane fraction of cells co-expressing Hyal-2 and CD44. The pH optimum for Hyal-2 was 6.0 -7.0. The membrane fraction of cells expressing Hyal-2 alone did not show hyaluronidase activity. Hyal-3 did not show any hyaluronidase activity in our experimental conditions. Based on these findings, Hyal-1 and -2 contribute to intracellular and extracellular catabolism of HA, respectively, in a CD44-dependent manner, and their HA degradation occurs independently from one another.Hyaluronic acid (HA) 3 is a negatively charged, high molecular weight glycosaminoglycan found predominantly in the extracellular matrix. It is the simplest of the glycosaminoglycans, the only one not covalently linked to core protein, and is unbranched and composed of repeating alternating units of glucuronic acid and N-acetylglucosamine. Despite the simplicity of its composition, HA has a great number of biological functions. It not only functions as a biological glue that participates in lubricating joints or holding together gel-like connective tissues, but also functions as a microenvironmental cue that co-regulates cell behavior during embryonic development and morphogenesis (1, 2), wound healing (3, 4), repair and regeneration, inflammation (5-7), and tumor progression and invasion (8, 9).There are 15 g of HA in a 70-kg individual, of which 5 g is replaced daily. In the skin, which contains 50% of the total body HA, the half-life of HA is about 1 day, and even in as seemingly inert a tissue as cartilage, HA turns over with a ha...

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“…Although there was no known oncogene in JSRV, the JSRV envelope (Env) protein was shown by us (3) and others (9) to transform rodent fibroblast cell lines. The cytoplasmic tail of Env, in particular a YXXM protein motif that is a putative docking site for phosphatidylinositol 3-kinase (PI3-kinase) after tyrosine phosphorylation, is important for fibroblast transformation, which seems to be mediated through the PI3-kinase͞Akt pathway (10,11).…”

mentioning

confidence: 99%

Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus

Danilkovitch‐Miagkova

Duh

Kuzmin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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The candidate tumor-suppressor gene hyaluronidase 2 (HYAL2) encodes a glycosylphosphatidylinositol-anchored cell-surface protein that serves as an entry receptor for jaagsiekte sheep retrovirus, a virus that causes contagious lung cancer in sheep that is morphologically similar to human bronchioloalveolar carcinoma. The viral envelope (Env) protein alone can transform cultured cells, and we hypothesized that Env could bind and sequester the HYAL2 receptor and thus liberate a potential oncogenic factor bound and negatively controlled by HYAL2. Here we show that the HYAL2 receptor protein is associated with the RON receptor tyrosine kinase (also called MST1R or Stk in the mouse), rendering it functionally silent. In human cells expressing a jaagsiekte sheep retrovirus Env transgene, the Env protein physically associates with HYAL2. RON liberated from the association with HYAL2 becomes functionally active and consequently activates the Akt and mitogen-activated protein kinase pathways leading to oncogenic transformation of immortalized human bronchial epithelial cells. We find activated RON in a subset of human bronchioloalveolar carcinoma tumors, suggesting RON involvement in this type of human lung cancer.

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Direct transformation of rodent fibroblasts by jaagsiekte sheep retrovirus DNA

Cited by 143 publications

References 26 publications

New transformation tricks from a barnyard retrovirus: Implications for human lung cancer

New transformation tricks from a barnyard retrovirus: Implications for human lung cancer

CD44-dependent Intracellular and Extracellular Catabolism of Hyaluronic Acid by Hyaluronidase-1 and -2

Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus

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