ライフサイエンスコーパス: JSRV

1 JSRV and ENTV are highly related but induce different di

2 JSRV and ENTV represent a unique class of oncogenic retr

3 JSRV encodes unspliced and spliced viral RNAs, among whi

4 JSRV Env was not found to disrupt polarity or tight junc

5 JSRV is unique among retroviruses because it transforms

6 JSRV is unique because the envelope gene (env) is the on

7 JSRV is unique in that the envelope protein functions as

8 JSRV(21) virus was obtained by transiently transfecting

9 JSRV, the causative agent of a transmissible lung cancer

10 port studies to determine whether the Hyal-2-JSRV Env interaction plays a role in virus-induced trans

11 Deletion of env sequences from a JSRV proviral expression plasmid (pTN3) abolished its ab

12 We previously isolated a JSRV proviral clone and showed that it was both infectio

13 Mutational analysis of a JSRV LTR reporter construct (pJS21luc) revealed that the

14 ng, pathogenicity, and integration site of a JSRV provirus isolated from a sheep lung tumor cell line

15 transient transfection of 293T cells with a JSRV construct (pCMV2JS21) in which the upstream U3 was

16 mmune recognition of Env can protect against JSRV tumorigenesis.

17 The results obtained indicated that ENTV and JSRV share the same receptor in sheep cells and that the

18 In summary, although ENTV and JSRV use the same cell surface receptor for cell entry a

19 s as an efficient receptor for both ENTV and JSRV.

20 sessed sequence differences between ESRV and JSRV.

21 the infected cells banded at 1.15 g/ml, and JSRV(21) provirus was transmitted from infected cells to

22 in sheep, and oncoretroviral vectors bearing JSRV Env can mediate transduction of human cells, sugges

23 Retroviral vectors bearing JSRV Env can transduce cells from a wide range of specie

24 al2 did not mediate entry of virions bearing JSRV or ENTV Env proteins, bound JSRV SU poorly if at al

25 erated a series of envelope chimeras between JSRV and the JSRV-related endogenous retroviruses of she

26 and the retrovirus, just as there is between JSRV and sheep pulmonary adenomatosis.

27 Chimeric Env proteins between JSRV and the unrelated murine retroviruses Moloney murin

28 ons bearing JSRV or ENTV Env proteins, bound JSRV SU poorly if at all, and did not suppress transform

29 an induce rapid, multifocal lung cancer, but JSRV is a simple retrovirus having no known oncogenes.

30 Lung cancer induced by JSRV closely resembles human bronchiolo-alveolar carcino

31 esponse of ovine lung tissue to infection by JSRV.

32 ial cell line, transformation is mediated by JSRV Env binding to Hyal2 followed by Hyal2 degradation

33 Most cells that are not transduced by JSRV or ENTV vectors can be made susceptible following e

34 caused a decrease in cell transformation by JSRV Env, while overexpression of Zfp111 increased overa

35 the involvement of PI3K in transformation by JSRV.

36 Akt was activated in cells transformed by JSRV or ENTV Env proteins and in cells transformed by th

37 rved MP1 cells (NIH 3T3 cells transformed by JSRV) but not in the parental NIH 3T3 cells.

38 and the exogenous infectious molecular clone JSRV(21).

39 Infection of concentrated JSRV(21) into ovine choroid plexus (CP), testes (OAT-T3)

40 limited to the Golgi apparatus and disrupts JSRV envelope (Env) trafficking by sequestering it.

41 virus entry using the same receptor as does JSRV Env, the candidate tumor suppressor Hyal2.

42 a more restricted range of species than does JSRV, and based on this finding we have identified amino

43 cate that domains in SU facilitate efficient JSRV transformation.

44 We previously showed that the gene encoding JSRV envelope protein (Env) appears to function as an on

45 The endogenous JSRVs (enJSRVs) are abundantly expressed in the uterine

46 noteworthy that p38 MAPK inhibitors enhanced JSRV transformation in both fibroblasts and epithelial c

47 the etiologic roles of ESRV and an exogenous JSRV-like retrovirus (exJSRV) in OPC, we assessed sequen

48 The exogenous JSRV and ENTV are the etiological agents of ovine pulmon

49 Chimeras containing the exogenous JSRV SU region and the enJSRV TM region were unable to t

50 e remaining portion of TM from the exogenous JSRV were also unable to transform NIH 3T3 cells.

51 Vs was found to block entry of the exogenous JSRV, presumably via mechanisms of receptor interference

52 tein and is transdominant over the exogenous JSRV.

53 JSRV groups A and B, ENTV, and two exogenous JSRV groups (African versus United Kingdom/North America

54 independence for growth, and they expressed JSRV RNA.

55 ion of human Hyal2 in mouse cells expressing JSRV Env caused a marked reduction in Env protein levels

56 virions from concentrated supernatant fluid, JSRV-associated OPC lesions were found in one of four la

57 ar lung-specific genes, may be important for JSRV expression in lung epithelial cells.

58 regions previously shown to be important for JSRV long terminal repeat (LTR) activity: a binding site

59 a lesser extent, Akt-mTOR) is important for JSRV-induced transformation and that p38 MAPK has a nega

60 nts indicated that PI3K is not necessary for JSRV-induced transformation: (i) cotransfection with a d

61 ne by transfecting an expression plasmid for JSRV [pCMVJS21, driven by the cytomegalovirus (CMV) imme

62 The resulting tumors were positive for JSRV DNA and protein.

63 ot been possible to study the host range for JSRV because of the inability to grow this virus in cult

64 er virus, we have studied the host range for JSRV, which includes sheep, human, monkey, bovine, dog,

65 The cellular receptor for JSRV is hyaluronidase 2 (Hyal-2), the product of a putat

66 onidase 2 (HYAL2), the cellular receptor for JSRV.

67 r suppressor HYAL2/LUCA2 as the receptor for JSRV.

68 While PI3K is not required for JSRV-induced transformation of NIH 3T3 cells, the downst

69 is at least one common integration site for JSRV in OPA and add weight to the hypothesis that insert

70 loci revealed restriction sites specific for JSRV.

71 Furthermore, JSRV Env can transform cultured cells by two distinct me

72 ep genome contains 15 to 20 copies of highly JSRV-related endogenous sequences that cross-react with

73 ved in MLE-15 cells only with the homologous JSRV promoter.

74 nv has the same properties as the homologous JSRV protein.

75 Immunoreactive JSRV capsid and envelope proteins were detected in the e

76 uggesting a possible involvement of PI-3K in JSRV and ENTV Env-induced cell transformation.

77 ,971 ovine genes differentially expressed in JSRV-infected lung compared to noninfected lung, includi

78 ses, suggesting a potential role of HYAL2 in JSRV Env-mediated oncogenesis.

79 study, we found that Akt/mTOR is involved in JSRV transformation of mouse NIH 3T3 fibroblasts, becaus

80 with JSRV Env in cells and to be involved in JSRV transformation.

81 as found to be activated (phosphorylated) in JSRV-transformed PI3K-negative cells.

82 -3K inhibitor blocked Akt phosphorylation in JSRV Env-transformed cells, suggesting a possible involv

83 into the role of the TM cytoplasmic tail in JSRV transformation.

84 e propagation of JSRV and (ii) an infectious JSRV molecular clone.

85 ibitors PD98059 and U0126 strongly inhibited JSRV transformation of NIH 3T3 fibroblasts, suggesting t

86 incorporation of envelope glycoprotein into JSRV viral particles, which in turn reduces virion infec

87 text of a cytomegalovirus-driven full-length JSRV expression construct abolished Gag protein synthesi

88 e etiology of SPA, we isolated a full-length JSRV proviral clone, pJSRV21, from a tumor genomic DNA l

89 Indeed, enJSRVs, like JSRV and ENTV, were found to utilize hyaluronidase-2 as

90 Interestingly, in most cell lines, JSRV expression plasmids with Rej deleted showed normal

91 ogenous sequences that cross-react with many JSRV hybridization probes.

92 Interestingly, an MMuLV-JSRV chimera in which the putative receptor binding doma

93 Cell lines derived from foci of MMuLV-JSRV chimera-transformed 208F cells grew in soft agar an

94 Moreover, JSRV-transformed cells show phosphorylation (activation)

95 Adaptation of JSRV to infection and replication in the lung and its ap

96 We recently isolated a proviral clone of JSRV from an animal with a spontaneous case of SPA (JSRV

97 Moreover, coexpression of JSRV Env and Zfp111 led to the identification of a novel

98 acity has direct relevance for the design of JSRV-based vectors that target the differentiated epithe

99 at least is not an essential determinant of JSRV-induced transformation of fibroblasts and that the

100 te internal splicing events in the 5' end of JSRV env that could signify analogous doubly spliced Rej

101 The envelope of JSRV may have oncogenic properties, since it can morphol

102 rentially bound to a higher-mobility form of JSRV Env that has not been described previously.

103 Here we show that the envelope (env) gene of JSRV has the unusual property that it can induce transfo

104 gar and showed Akt activation, a hallmark of JSRV-transformed rodent fibroblasts.

105 Sheep are immunotolerant of JSRV because of the expression of closely related endoge

106 in cells that do not support a high level of JSRV expression.

107 or further investigation of the mechanism of JSRV oncogenesis and its relationship to human bronchiol

108 The molecular mechanisms of JSRV Env transformation are of considerable interest.

109 To further investigate the mechanisms of JSRV oncogenesis, we generated a series of envelope chim

110 could not detect tyrosine phosphorylation of JSRV or ENTV Env proteins or an interaction between the

111 tissue culture system for the propagation of JSRV and (ii) an infectious JSRV molecular clone.

112 ppress transformation by the Env proteins of JSRV and ENTV.

113 We tested the Env proteins of JSRV and MMTV, as well as human endogenous retrovirus K

114 omain (RBD) and proline-rich region (PRR) of JSRV Env were replaced by the RBD and PRR of MMuLV induc

115 The host range of JSRV is in part limited by species-specific differences

116 while it decreased the proliferation rate of JSRV-transformed 208F cells, suggesting that JSRV-transf

117 the C-terminal heptad repeat (HR2) region of JSRV and ENTV Envs, particularly proximal to the hairpin

118 es prepared from the envelope (SU) region of JSRV and the capsid (CA) region of a Peruvian type D vir

119 ce for binding of the surface (SU) region of JSRV Env to human and rat Hyal2.

120 l types and that the observed restriction of JSRV expression in vivo to tumor cells might be controll

121 To investigate the role of JSRV in the etiology of SPA, we isolated a full-length J

122 udy, we investigated the cell specificity of JSRV expression.

123 ced for the original South African strain of JSRV.

124 d mouse fibroblasts, the cytoplasmic tail of JSRV Env is essential for transformation, which involves

125 matic mutagenesis of the cytoplasmic tail of JSRV Env.

126 a restricted host range compared to that of JSRV.

127 iruses in tumors strongly resembled those of JSRV but differed from those of ESRVs, suggesting that e

128 of different breeds were similar to those of JSRV in structural genes but divergent in U3.

129 B impairs the normal cellular trafficking of JSRV envelope glycoproteins by sequestering them within

130 , nor did the drug reverse transformation of JSRV-transformed cells.

131 of lung fluid suggest that vectors based on JSRV would be useful for gene therapy targeted to the lu

132 A major impediment in research on JSRV has been the lack of an in vitro tissue culture sys

133 f the virus was 93 to 99% identical to other JSRV isolates and contained all of the expected open rea

134 We prepared JSRV particles by transient transfection of 293T cells w

135 d the MoMLV Gag-Pol proteins and can produce JSRV-pseudotype vectors at titers of up to 10(6) alkalin

136 and test its infectivity, the JS7 provirus (JSRV(JS7)) was cloned into a plasmid containing a cytome

137 e gene (env) of Jaagsiekte sheep retrovirus (JSRV) also acts as an oncogene.

138 Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) are simple b

139 etaretroviruses jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) cause contag

140 Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) induce epith

141 genous viruses, Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), and a group

142 d retroviruses, jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), is responsi

143 viruses include Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV).

144 ogenic viruses, jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV).

145 o the oncogenic jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus.

146 genus includes Jaagsiekte sheep retrovirus (JSRV) and mouse mammary tumor virus (MMTV), as well as m

147 irus (ENTV) and jaagsiekte sheep retrovirus (JSRV) are closely related retroviruses that cause epithe

148 Jaagsiekte sheep retrovirus (JSRV) can induce rapid, multifocal lung cancer, but JSRV

149 Jaagsiekte sheep retrovirus (JSRV) causes a contagious lung cancer in sheep and goats

150 betaretrovirus Jaagsiekte sheep retrovirus (JSRV) encodes within the env gene a trans-acting factor

151 Jaagsiekte sheep retrovirus (JSRV) induces bronchioalveolar tumors in sheep and goats

152 Jaagsiekte sheep retrovirus (JSRV) infects lung epithelial cells in sheep, and oncore

153 Jaagsiekte sheep retrovirus (JSRV) is a simple betaretrovirus causing a contagious lu

154 Jaagsiekte sheep retrovirus (JSRV) is a type D retrovirus associated with a contagiou

155 Jaagsiekte sheep retrovirus (JSRV) is an exogenous retrovirus of sheep that induces a

156 rotein (Env) of Jaagsiekte sheep retrovirus (JSRV) is an oncogene, but its mechanism of cell transfor

157 Jaagsiekte sheep retrovirus (JSRV) is the causative agent of a contagious lung cancer

158 Jaagsiekte sheep retrovirus (JSRV) is the causative agent of a transmissible lung can

159 Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocar

160 Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocar

161 Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocar

162 Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary carcinom

163 Jaagsiekte sheep retrovirus (JSRV) is the etiologic agent of a contagious bronchioloa

164 Jaagsiekte sheep retrovirus (JSRV) is the etiologic agent of a transmissible lung can

165 Jaagsiekte sheep retrovirus (JSRV) is the etiologic agent of ovine pulmonary adenocar

166 Jaagsiekte sheep retrovirus (JSRV) is the etiological agent of a contagious lung canc

167 sely related to Jaagsiekte sheep retrovirus (JSRV) is ubiquitous in domestic and wild sheep and goats

168 The jaagsiekte sheep retrovirus (JSRV) receptor, hyaluronidase 2 (Hyal2), is a glycosylph

169 Jaagsiekte sheep retrovirus (JSRV) replicates in the lungs of sheep and causes the se

170 Jaagsiekte sheep retrovirus (JSRV) uses hyaluronidase 2 (Hyal2) as a cell entry recep

171 virus, known as jaagsiekte sheep retrovirus (JSRV), has been associated with the etiology of SPA, but

172 etaretroviruses Jaagsiekte sheep retrovirus (JSRV), mouse mammary tumor virus (MMTV), and consensus h

173 sely related to jaagsiekte sheep retrovirus (JSRV), which also causes cancer in sheep but in the epit

174 The jaagsiekte sheep retrovirus (JSRV), which appears to be a type B/D retrovirus chimera

175 tivity with the jaagsiekte sheep retrovirus (JSRV), which is associated with a contagious lung tumor

176 sheep caused by jaagsiekte sheep retrovirus (JSRV).

177 ric retrovirus, jaagsiekte sheep retrovirus (JSRV).

178 ovirus known as jaagsiekte sheep retrovirus (JSRV).

179 virus of sheep, jaagsiekte sheep retrovirus (JSRV).

180 s and oncogenic jaagsiekte sheep retrovirus (JSRV).

181 s and oncogenic Jaagsiekte sheep retrovirus (JSRV).

182 sheep caused by Jaagsiekte sheep retrovirus (JSRV).

183 e D retrovirus (jaagsiekte sheep retrovirus [JSRV]) as the causative agent of SPA.

184 l exit of the Jaagsiekte sheep retroviruses (JSRV), most probably by retaining virions at the cell me

185 he transfected animals by a highly sensitive JSRV-U3 heminested PCR at various time points ranging fr

186 Other than sheep, JSRV is known to infect goats, but there is no evidence

187 om an animal with a spontaneous case of SPA (JSRV(21)) and showed that it harbors an infectious and o

188 found in one of four lambs, confirming that JSRV(JS7) is pathogenic.

189 This demonstrated that JSRV is necessary and sufficient to induce SPA.

190 The finding that JSRV env is oncogenic and the identification of HYAL2 as

191 In another study we found that JSRV encodes a regulatory protein, Rej, that is responsi

192 To test the hypothesis that JSRV insertional mutagenesis is involved in the oncogene

193 These results indicate that JSRV transformation also involves proteins and interacti

194 The results indicated that JSRV Env-transformed MDCK cells were larger and had full

195 iments with [(35)S]methionine indicated that JSRV Rej is required for the synthesis of viral Gag poly

196 from 27 of the hybrid lines, indicating that JSRV gag sequences are found on at least 15 of the 28 sh

197 d by standard disinfectants, indicating that JSRV vectors pose no unusual safety risk related to thei

198 Here we show that JSRV and ENTV Env proteins can also transform Madin-Darb

199 Here we show that JSRV and ENTV Env proteins with tyrosine or methionine m

200 Here we show that JSRV Env can also efficiently pseudotype a human immunod

201 These results suggest that JSRV Env transformation may involve nuclear events such

202 JSRV-transformed 208F cells, suggesting that JSRV-transformed cells became dependent on Zfp111.

203 The JSRV enhancers are able to activate heterologous promote

204 the JSRV enhancers are able to activate the JSRV proximal promoter in MLE-15 and mtCC1-2 cells, but

205 action between the enhancer elements and the JSRV proximal promoter elements.

206 es of envelope chimeras between JSRV and the JSRV-related endogenous retroviruses of sheep (enJSRVs)

207 genic and the identification of HYAL2 as the JSRV receptor provide tools for further investigation of

208 ow here that a retrovirus vector bearing the JSRV Env is stable during treatment with lung surfactant

209 Moloney murine leukemia virus driven by the JSRV enhancers (DeltaMo+JS Mo-MuLV).

210 e identical to that of tumors induced by the JSRV Env, indicating that factors other than Env mediate

211 lines with a reporter plasmid driven by the JSRV long terminal repeat (LTR), pJS21-luc, we found tha

212 , and did not suppress transformation by the JSRV or ENTV Env proteins, indicating that mouse Hyal2 p

213 vation in cells that were transformed by the JSRV or ENTV Env proteins.

214 man 293T cells with a plasmid containing the JSRV(21) provirus driven by the human cytomegalovirus im

215 troviral vectors pseudotyped with either the JSRV or the ENTV Env and sheep choroid plexus cells, cho

216 retrovirus packaging cells that express the JSRV Env and the MoMLV Gag-Pol proteins and can produce

217 , choroid plexus cells stably expressing the JSRV Env protein, human 293T cells, mouse NIH 3T3 cells,

218 Finally the JSRV(21) LTR contains putative enhancer binding motifs f

219 mally show minimal enhancer activity for the JSRV LTR.

220 contrast, a single domain is modeled for the JSRV, MMTV, and HERV-K betaretrovirus envelope proteins

221 Furthermore, the JSRV vector was stable during centrifugation, allowing f

222 However, the JSRV vector was inactivated by standard disinfectants, i

223 In vivo footprints were found in the JSRV enhancers in two regions previously shown to be imp

224 radiation hybrids to phenotypically map the JSRV receptor (JVR) gene within the p21.3 region of huma

225 s suggested that the cytoplasmic tail of the JSRV Env mediates transformation, possibly via a cell si

226 dentification of a novel nuclear form of the JSRV Env protein that binds Zfp111.

227 Expression of the JSRV envelope (Env) induces transformation of rodent fib

228 ly, we have found that the expression of the JSRV envelope (Env) is sufficient to transform mouse NIH

229 Here we show that expression of the JSRV envelope (Env) protein alone in lungs of mice, by u

230 Expression of the JSRV envelope (Env) protein in mouse airway epithelial c

231 The affinities of the JSRV envelope glycoprotein for Hyal2 and the Hyal2 mutan

232 Expression of the JSRV envelope protein (Env) is sufficient to transform i

233 he ability to dissociate the function of the JSRV envelope to mediate viral entry from its transformi

234 Y590 and M593 in the cytoplasmic tail of the JSRV envelope were sufficient to inhibit the transformin

235 Inspection of the JSRV genome reveals standard retroviral genes, but no ev

236 Substitution of the JSRV Leu with a Val blocked the Env-mediated membrane fu

237 be responsible for approximately 50% of the JSRV LTR transcriptional activity in MLE-15 cells.

238 The oncogenic significance of the JSRV proviral insertion involving the SP-A locus in the

239 -spanning region and cytoplasmic tail of the JSRV TM glycoprotein; this suggested that the cytoplasmi

240 ta indicate that the cytoplasmic tail of the JSRV TM is necessary for cell transformation and suggest

241 Considering the inability of the JSRV-pseudotype vector to transduce hamster cells, we us

242 These results show that the JSRV and ENTV Env proteins can transform epithelial cell

243 se results suggested the hypothesis that the JSRV and ENTV Env proteins cause cancer by inhibiting th

244 f pJS21-luc allowed us to establish that the JSRV enhancers are able to activate the JSRV proximal pr

245 Here we show that the JSRV envelope protein (Env) can be used to pseudotype Mo

246 rs rapidly, and we previously found that the JSRV envelope protein (Env) functions as an oncogene, be

247 l repeat (LTR), pJS21-luc, we found that the JSRV LTR is preferentially active in cell lines derived

248 however, careful examination shows that the JSRV receptor does not colocalize with any of these gene

249 These results suggest that the JSRV receptor is present on many ovine cell types and th

250 Thus, the JSRV TM is necessary and sufficient to transform rodent

251 cellular protein, Zfp111, that binds to the JSRV Env protein, and this binding plays a role in Env t

252 n vitro infection with this virus, using the JSRV(21) clone.

253 We tested whether the JSRV genome might encode a transforming gene by transfec

254 As with the JSRV Env, the tyrosine at position 590 is critical for E

255 Interaction of sHyal2 with the JSRV envelope glycoprotein was analyzed by viral inhibit

256 duced DNA fragments that hybridized with the JSRV gag probe, but neither lung DNAs from healthy sheep

257 Therefore, JSRV envelope can induce PI3K-independent phosphorylatio

258 To address this, JSRV Env transformation was studied in the context of ep

259 Thus JSRV is necessary and sufficient for the development of

260 Thus, JSRV cell-specific LTR activity appears to result from a

261 eep retrovirus (ESRV) loci that hybridize to JSRV DNA probes.

262 B and type D retroviral sequences related to JSRV among mammals and argue for further investigation o

263 ootic nasal tumor virus (ENTV) is related to JSRV but induces tumors in the nasal epithelium of sheep

264 region of a Peruvian type D virus related to JSRV were used in Southern blot hybridization with genom

265 id level, that this retrovirus is related to JSRV yet apparently distinct from it.

266 rious mammal groups for sequences related to JSRV.

267 ession that occur in the lung in response to JSRV infection.

268 not show an appreciable antibody response to JSRV or ENTV.

269 This suggests that the pulmonary tropic JSRV developed from a type D retrovirus that did not hav

270 deleted showed normal transport of unspliced JSRV RNA to the cytoplasm; however, in 293T cells Rej mo

271 a cells) of the lungs; these cells are where JSRV is specifically expressed in both naturally and exp

272 Here we show that as with JSRV, the envelope (Env) protein of ENTV can transform c

273 ate cellular proteins that can interact with JSRV Env by yeast two-hybrid screening.

274 Zfp111 was shown to interact with JSRV Env in cells and to be involved in JSRV transformat

275 defect in exit and ability to interfere with JSRV exit could be largely attributed to the presence of

276 he lines was used as a template for PCR with JSRV gag-specific primers.

277 5alpha and p85beta could be transformed with JSRV envelope, and (iv) incubation of cells with the PI3

278 lls transfected by enJS56A1, with or without JSRV, show agglomerates of tightly packed intracellular