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

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

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

34 the involvement of PI3K in transformation by JSRV.

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

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

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

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

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

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

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

42 cate that domains in SU facilitate efficient JSRV transformation.

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

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

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

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

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

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

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

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

51 tein and is transdominant over the exogenous JSRV.

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

53 independence for growth, and they expressed JSRV RNA.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

69 loci revealed restriction sites specific for JSRV.

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

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

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

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

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

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

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

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

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

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

80 -3K inhibitor blocked Akt phosphorylation in JSRV Env-transformed cells, suggesting a possible involv

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

121 ced for the original South African strain of JSRV.

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

123 matic mutagenesis of the cytoplasmic tail of JSRV Env.

124 a restricted host range compared to that of JSRV.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 carcinom

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

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

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

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

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

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

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

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

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

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

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

172 ric retrovirus, jaagsiekte sheep retrovirus (JSRV).

173 s and oncogenic jaagsiekte sheep retrovirus (JSRV).

174 ovirus known as jaagsiekte sheep retrovirus (JSRV).

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

176 s and oncogenic Jaagsiekte sheep retrovirus (JSRV).

177 sheep caused by Jaagsiekte sheep retrovirus (JSRV).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

198 The JSRV enhancers are able to activate heterologous promote

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

214 mally show minimal enhancer activity for the JSRV LTR.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

251 Therefore, JSRV envelope can induce PI3K-independent phosphorylatio

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

253 Thus JSRV is necessary and sufficient for the development of

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

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

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

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

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

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

260 rious mammal groups for sequences related to JSRV.

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

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

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

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

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

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

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

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

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

270 5alpha and p85beta could be transformed with JSRV envelope, and (iv) incubation of cells with the PI3

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