ライフサイエンスコーパス: iPLA(2)

1 astatic breast cancer cells by inhibition of iPLA2.

2 IVA cPLA2 and calcium-independent Group VIA iPLA2.

3 inhibitors inhibited either GV sPLA2 or GVIA iPLA2.

4 PLA2 enzymes: group IVA cPLA2 and group VIA iPLA2.

5 h higher potency and selectivity toward GVIA iPLA2.

6 man Group VIA calcium-independent PLA2 (GVIA iPLA2).

7 s by inhibition of calcium-independent PLA2 (iPLA2).

8 d activation of overexpressed and endogenous iPLA(2).

9 s that selectively and weakly inhibited GVIA iPLA(2).

10 pporting that the major target of action was iPLA(2).

11 1), but not beta(4), integrin is involved in iPLA(2) activation and cell migration to laminin-10/11.

12 tify novel signaling and functional loops of iPLA(2) activation leading to migration of non-apoptotic

13 , and PCR confirmed that there was increased iPLA(2) activity and expression in neutrophils from peop

14 Moreover, increases in iPLA(2) activity and iPLA(2)beta protein expression are

15 ose increases iPLA(2)beta mRNA, protein, and iPLA(2) activity in a time-dependent manner.

16 key roles in recruiting and modulating GVIA-iPLA(2) activity in cells.

17 calcium-independent phospholipase A2 (Ca(2+)-iPLA2) activity by MJ33 on fertilization competence of m

18 amma-KO mice showed no alteration in cardiac iPLA2 activity and produced less PGE2.

19 MJ33 inhibited the PRDX6 Ca(2+)-iPLA2 activity and reduced these parameters in WT sperma

20 nclusion, the inhibition of the PRDX6 Ca(2+)-iPLA2 activity promotes an oxidative stress affecting vi

21 A significant increase in iPLA2 activity was observed in WT mice following infecti

22 ively inhibiting calcium-independent PLA(2) (iPLA(2)) activity and absent in macrophages isolated fro

23 Although the most potent inhibitors of GVIA iPLA(2) also inhibited GIVA cPLA(2), there were three 2-

24 The truncated iPLA(2) (amino acids 514-806) generates lysophosphatidic

25 g free carboxylic groups do not inhibit GVIA iPLA(2) and are, therefore, selective GIVA cPLA(2) inhib

26 ty and sequence mutations on the activity of iPLA(2) and related enzymes.

27 lipid signaling molecules, such as LPA, via iPLA(2) and/or cPLA(2) activities.

28 of a calcium-independent phospholipase A(2) (iPLA(2)), and this leads to arachidonic acid release and

29 so examined and shown to be increased via an iPLA(2)- and LOX-dependent pathway.

30 and the calcium-independent PLA2s (cPLA2 and iPLA2), are key enzymes mediating oligomeric amyloid-bet

31 propose the first structural model of GVIA-2 iPLA(2) as well as the interfacial lipid binding region.

32 A modified iPLA(2) assay, Western blotting, and PCR confirmed that

33 ia even before apoptotic induction, and most iPLA2-associated mitochondria were intact in apoptotic r

34 our approach is suitable for the modeling of iPLA(2) at the membrane surface.

35 vity and absent in macrophages isolated from iPLA(2) beta(-/-) mice.

36 eversal of calmodulin-mediated inhibition of iPLA2 beta phospholipase A2 activity.

37 possibility, we find that ER stress promotes iPLA(2)beta accumulation in the mitochondria, opening of

38 from different intracellular locations, with iPLA(2)beta acting as a critical regulator of the cellul

39 pecific molecular causes and consequences of iPLA(2)beta activation are not known.

40 es or thapsigargin, that this requires prior iPLA(2)beta activation, and that p38 MAPK is involved in

41 at actions of PKC and PKA precede and follow iPLA(2)beta activation, respectively.

42 ng signaling events that occur downstream of iPLA(2)beta activation, we found that p38 MAPK is activa

43 ed by pharmacologic or genetic reductions in iPLA(2)beta activity and amplified by iPLA(2)beta overex

44 , all of which were suppressed by inhibiting iPLA(2)beta activity or expression with bromoenol lacton

45 Inhibiting iPLA(2)beta activity with bromoenol lactone or preventin

46 lial PAF production is entirely dependent on iPLA(2)beta activity.

47 DN)-treated monocytes display reduced speed, iPLA(2)beta also regulates directionality and actin poly

48 iPLA(2)beta and any associated proteins were then displa

49 amide generation, but the mechanism by which iPLA(2)beta and ceramides contribute to apoptosis is not

50 These converging observations reveal that iPLA(2)beta and cPLA(2)alpha regulate monocyte migration

51 To elucidate the association between iPLA(2)beta and ER stress, we compared beta-cell lines g

52 activated by the store-operated pathway, and iPLA(2)beta as an essential component of signal transduc

53 These data confirm the role of iPLA(2)beta as an essential mediator of endogenous SOCE

54 Immunoblotting studies indicate that iPLA(2)beta associates with mitochondria in macrophages

55 Phosphorylation of iPLA(2)beta at Tyr(616) also occurs upon induction of ER

56 i1 and a specific plasma membrane variant of iPLA(2)beta but not STIM1.

57 d to study iPLA(2)beta functions inactivates iPLA(2)beta by alkylating Cys thiols.

58 origin, our findings suggest that absence of iPLA(2)beta causes abnormalities in osteoblast function

59 These results indicate that loss of iPLA(2)beta causes age-dependent impairment of axonal me

60 ersible inactivation because oxidant-treated iPLA(2)beta contains DTT-reducible oligomers, and oligom

61 by FCL or thapsigargin but that deletion of iPLA(2)beta does not impair macrophage arachidonate inco

62 lls and suppresses increases in mSREBP-1 and iPLA(2)beta due to thapsigargin.

63 te that smooth muscle-specific expression of iPLA(2)beta exacerbates ligation-induced neointima forma

64 l migration and invasion with cells in which iPLA(2)beta expression had been down-regulated in vitro.

65 Here, we report that iPLA(2)beta expression increases in the vascular tunica

66 pancreatic islets, that this increases with iPLA(2)beta expression level, and that it is stimulated

67 nd increases toward WT levels upon restoring iPLA(2)beta expression.

68 actone (BEL) suicide substrate used to study iPLA(2)beta functions inactivates iPLA(2)beta by alkylat

69 the possibility that redox reactions affect iPLA(2)beta functions.

70 The iPLA(2)beta gene contains a sterol-regulatory element, a

71 bind to the sterol-regulatory element in the iPLA(2)beta gene to promote its transcription.

72 ree fatty acid and a 2-lysophospholipid, and iPLA(2)beta has been reported to participate in apoptosi

73 bly transfected INS-1 cells that overexpress iPLA(2)beta hydrolyze phospholipids more rapidly than co

74 Molecular knockdown of iPLA(2)beta impaired SOCE in both control cells and cell

75 ate that p38 MAPK is activated downstream of iPLA(2)beta in beta-cells incubated with insulin secreta

76 d identify a previously unrecognized role of iPLA(2)beta in bone formation.

77 first demonstration of a role for host cell iPLA(2)beta in cancer, and these findings suggest that i

78 rombin and tryptase to determine the role of iPLA(2)beta in endothelial cell membrane phospholipid hy

79 To explore the role of iPLA(2)beta in host-tumor cell interactions, we have use

80 and forskolin is amplified by overexpressing iPLA(2)beta in INS-1 cells and in mouse islets, and the

81 I-17 activation, and restoring expression of iPLA(2)beta in iPLA(2)beta-deficient cells also restores

82 negative SREBP-1 reduces basal mSREBP-1 and iPLA(2)beta in the Akita cells and suppresses increases

83 mplex relationships between Orai1, STIM1 and iPLA(2)beta in the SOCE pathway.

84 The activity of iPLA(2)beta in vitro increases upon co-incubation with c

85 occurs with time- and temperature-dependent iPLA(2)beta inactivation that is attenuated by DTT or AT

86 R chaperone calnexin, whose association with iPLA(2)beta increases upon induction of ER stress.

87 se-induced CPI-17 phosphorylation similar to iPLA(2)beta inhibition.

88 ctor-transfected cells, and is suppressed by iPLA(2)beta inhibition.

89 hosphorylation, and this is prevented by the iPLA(2)beta inhibitor bromoenol lactone.

90 kinase IIbeta, and we have characterized the iPLA(2)beta interactome further using affinity capture a

91 It has also been suggested that iPLA(2)beta is a housekeeping enzyme that regulates cell

92 a in cancer, and these findings suggest that iPLA(2)beta is a potential target for developing novel a

93 We conclude that iPLA(2)beta is an important mediator of AA release and p

94 ation, we generated transgenic mice in which iPLA(2)beta is expressed specifically in smooth muscle c

95 o investigate whether smooth muscle-specific iPLA(2)beta is involved in neointima formation, we gener

96 Upon MCP-1 stimulation, iPLA(2)beta is recruited to the membrane-enriched pseudo

97 ed iPLA(2)beta(-/-) mice to demonstrate that iPLA(2)beta is responsible for the majority of thapsigar

98 l interactions, we have used immunocompetent iPLA(2)beta knockout (iPLA(2)beta(-/-)) mice and the mou

99 >50% and were reduced further when ID8 cell iPLA(2)beta levels were lowered (by>95%) with shRNA.

100 n circulating cells, these data suggest that iPLA(2)beta may be a suitable therapeutic target for the

101 ion and neointima formation and suggest that iPLA(2)beta may represent a novel therapeutic target for

102 Recent reports indicate that iPLA(2)beta modulates mitochondrial cytochrome c release

103 rticipates in a variety of signaling events; iPLA(2)beta mRNA is expressed in bones of wild-type (WT)

104 We demonstrate that high glucose increases iPLA(2)beta mRNA, protein, and iPLA(2) activity in a tim

105 insulinoma cells to oxidative stress induces iPLA(2)beta oligomerization, loss of activity, and subce

106 rmation is suppressed by genetic deletion of iPLA(2)beta or by inhibiting its activity or expression

107 iPLA(2)beta or cPLA(2)alpha antisense ODN-treated adopti

108 Although iPLA(2)beta or cPLA(2)alpha antisense oligodeoxyribonucl

109 In support, inhibition of iPLA(2)beta or NSMase prevents cytochrome c release.

110 by forskolin, as well as by inactivation of iPLA(2)beta or NSMase, suggesting that iPLA(2)beta-media

111 Ca(2+)-independent phospholipase A(2) beta (iPLA(2)beta or PLA2g6A), or depletion of plasma membrane

112 but only caspase-3 cleavage is amplified in iPLA(2)beta overexpressing INS-1 cells (OE), relative to

113 ons in iPLA(2)beta activity and amplified by iPLA(2)beta overexpression.

114 These findings raise the likelihood that iPLA(2)beta participates in ER stress-induced apoptosis

115 These findings suggest that iPLA(2)beta participates in ER stress-induced macrophage

116 tic islets and insulinoma cells suggest that iPLA(2)beta participates in insulin secretion.

117 illustrate that smooth muscle cell-specific iPLA(2)beta participates in the initiation and early pro

118 of insulin secretion and apoptosis in which iPLA(2)beta participates.

119 tion and nuclear localization are blocked by iPLA(2)beta pharmacologic inhibition or genetic ablation

120 ed fatty acids, including AA, and inhibiting iPLA(2)beta prevents the muscarinic agonist-induced acce

121 Others have reported that iPLA(2)beta products activate Rho family G-proteins that

122 Moreover, increases in iPLA(2) activity and iPLA(2)beta protein expression are also observed in both

123 Expression of iPLA(2)beta protein in cultured vascular smooth muscle c

124 kinase C is involved in high glucose-induced iPLA(2)beta protein up-regulation.

125 sion level, and that it is stimulated by the iPLA(2)beta reaction product arachidonic acid.

126 selective), but not its enantiomer, (S)-BEL (iPLA(2)beta selective) or pyrrolidine (cytosolic PLA(2)a

127 Transfection of Akita cells with iPLA(2)beta small interfering RNA, however, suppresses N

128 h glucose-induced, protein kinase C-mediated iPLA(2)beta up-regulation activates the RhoA/Rho kinase/

129 tic SMCs that was dramatically attenuated in iPLA(2)beta(-/-) mice (>80% reduction at 5 min; p < 0.01

130 enesis and ascites formation were reduced in iPLA(2)beta(-/-) mice compared with wild-type (WT) mice

131 Moreover, iPLA(2)beta(-/-) mice displayed defects in SMC Ca(2+) ho

132 Accordingly, we used iPLA(2)beta(-/-) mice to demonstrate that iPLA(2)beta is

133 reduced to approximately 80% of WT levels in iPLA(2)beta(-/-) mice.

134 y approximately 5-fold) and tumorigenesis in iPLA(2)beta(-/-) mice.

135 alone rescued proliferation and migration in iPLA(2)beta(-/-) mice.

136 rescue of SMC migration and proliferation in iPLA(2)beta(-/-) mice.

137 affect Kv2.1 inactivation in beta-cells from iPLA(2)beta(-/-) mice.

138 e used immunocompetent iPLA(2)beta knockout (iPLA(2)beta(-/-)) mice and the mouse EOC cell line ID8.

139 anipulation of Group VIA phospholipase A(2) (iPLA(2)beta) activity in pancreatic islets and insulinom

140 hemotaxis, Ca(2+)-independent phospholipase (iPLA(2)beta) and cytosolic phospholipase (cPLA(2)alpha),

141 Group VIA phospholipase A(2) (iPLA(2)beta) hydrolyzes beta-cell membrane phospholipids

142 The Group VIA phospholipase A(2) (iPLA(2)beta) hydrolyzes glycerophospholipids at the sn-2

143 Group VIA phospholipase A(2) (iPLA(2)beta) in pancreatic islet beta-cells participates

144 Group VIA phospholipase A(2) (iPLA(2)beta) is expressed in phagocytes, vascular cells,

145 Whether group VIA phospholipase A(2) (iPLA(2)beta) is involved in vascular inflammation and ne

146 calcium-independent phospholipase A(2)beta (iPLA(2)beta) is required for high glucose-induced RhoA/R

147 reported that Group VIA phospholipase A(2) (iPLA(2)beta) is required for this response, but the spec

148 up VIA calcium-independent phospholipase A2 (iPLA(2)beta), were recently identified in patients with

149 kout (KO) mice lacking the group VIA PLA(2) (iPLA(2)beta), which participates in a variety of signali

150 lving Ca(2+)-independent phospholipase A(2) (iPLA(2)beta)-mediated ceramide generation, but the mecha

151 by a Ca(2+)-independent phospholipase A(2) (iPLA(2)beta)-mediated mechanism that promotes ceramide g

152 [calcium-independent phospholipase A(2)beta (iPLA(2)beta)] is important in regulating extracellular l

153 s identified 37 proteins that associate with iPLA(2)beta, and nearly half of them reside in ER or mit

154 Consistent with this, SREBP-1, iPLA(2)beta, and NSMase messages in Akita mouse islets a

155 rations of H(2)O(2), NO, and HOCl inactivate iPLA(2)beta, and this can be partially reversed by dithi

156 on the functional roles of Orai1, STIM1 and iPLA(2)beta, and will address some specific questions ab

157 Pharmacological and genetic inhibition of iPLA(2)beta, but not iPLA(2)gamma, diminishes diabetes-a

158 Regulatory proteins interact with iPLA(2)beta, including the Ca(2+)/calmodulin-dependent p

159 Interestingly, basal iPLA(2)beta, mature SREBP-1 (mSREBP-1), phosphorylated A

160 ta cells and is associated with increases in iPLA(2)beta, mSREBP-1, and NSMase in both WT and Akita c

161 lar myocytes with SERCA inhibitors activates iPLA(2)beta, resulting in hydrolysis of arachidonic acid

162 esults in augmentation of ER stress-induced, iPLA(2)beta-catalyzed hydrolysis of arachidonic acid fro

163 Collectively, our findings indicate that the iPLA(2)beta-ceramide axis plays a critical role in activ

164 , and restoring expression of iPLA(2)beta in iPLA(2)beta-deficient cells also restores high glucose-i

165 An iPLA(2)beta-FLAG fusion protein was expressed in an INS-

166 mulated lung endothelial cells isolated from iPLA(2)beta-knockout (KO) and wild type (WT) mice with t

167 red PLA(2) activity and PGI(2) production by iPLA(2)beta-KO cells were suppressed by pretreatment wit

168 release and PGI(2) production by stimulated iPLA(2)beta-KO endothelial cells were significantly redu

169 iPLA(2)beta-KO mice developed age-dependent neurological

170 We used iPLA(2)beta-KO mice generated by homologous recombinatio

171 iPLA(2)beta-KO mice will be useful for further studies o

172 on of iPLA(2)beta or NSMase, suggesting that iPLA(2)beta-mediated generation of ceramides via sphingo

173 ting and fed blood glucose concentrations of iPLA(2)beta-null and wild-type mice are essentially iden

174 aortic SMCs that was significantly slower in iPLA(2)beta-null cells (p < 0.01).

175 cytosol and that these events are blunted in iPLA(2)beta-null cells.

176 H]AA release upon FCL, this is attenuated in iPLA(2)beta-null macrophages and increases toward WT lev

177 iPLA(2)beta-null macrophages are also less sensitive to

178 beta-null mice, and here we demonstrate that iPLA(2)beta-null macrophages have reduced sensitivity to

179 WT and iPLA(2)beta-null macrophages incorporate [(3)H]arachidon

180 lycerophosphocholine lipids is unimpaired in iPLA(2)beta-null macrophages upon electrospray ionizatio

181 Furthermore, SMCs from iPLA(2)beta-null mesenteric arterial explants demonstrat

182 We have generated iPLA(2)beta-null mice by homologous recombination and ha

183 ly identical under normal circumstances, but iPLA(2)beta-null mice develop more severe hyperglycemia

184 ese and previous findings thus indicate that iPLA(2)beta-null mice exhibit phenotypic abnormalities i

185 Here we report that pancreatic islets from iPLA(2)beta-null mice have impaired insulin secretory re

186 o induces more severe glucose intolerance in iPLA(2)beta-null mice than in wild-type mice, but PLA(2)

187 We recently generated iPLA(2)beta-null mice, and here we demonstrate that iPLA

188 in bone mass and strength are accelerated in iPLA(2)beta-null mice.

189 he defects in migration and proliferation in iPLA(2)beta-null SMCs were restored by 2 mum AA.

190 er receptor A ligand fucoidan, and restoring iPLA(2)betaexpression with recombinant adenovirus increa

191 We have developed inhibitors of GVIA iPLA(2) building upon the 2-oxoamide backbone that are u

192 p VIA Ca(2+)-independent phospholipase A(2) (iPLA(2)) by fluoroketone (FK) ligands is examined by a c

193 iPLA(2) can be activated by caspase-3 via a proteolytic

194 ether, our results identify a novel role for iPLA(2)-catalyzed AA release and its metabolism by 12/15

195 sphorylation and is diminished by inhibiting iPLA(2), cyclooxygenase, or lipoxygenase.

196 icantly advance our understanding of the CIF-iPLA2-dependent mechanism of activation of ICRAC and sto

197 These studies indicate that iPLA2-dependent metabolic pathways play an important rol

198 t not iPLA2beta-null VSMC, Ang II stimulates iPLA2 enzymatic activity significantly.

199 the closest C. elegans homolog of human GVIA-iPLA(2) enzymes and use a combination of liposome intera

200 We show that iPLA2-expressing cells were relatively resistant to STS-

201 genous iPLA2 transcription in both INS-1 and iPLA2-expressing INS-1 cells without affecting the expre

202 g RNA-mediated down-regulation of endogenous iPLA(2) expression in ovarian carcinoma HEY cells result

203 recent identification of new members of the iPLA(2) family, each inhibitable by (E)-6-(bromomethylen

204 ed by inhibitors of the calcium-independent (iPLA2) form of the enzyme, whereas responses to menthol

205 for acidic phospholipids in regulating GVIA-iPLA(2) function.

206 Moreover, Ca(2+)-induced iPLA(2)gamma activation was accompanied by the productio

207 Intriguingly, Ca(2+)-induced iPLA(2)gamma activation was completely inhibited by long

208 This study addresses the mechanisms of iPLA(2)gamma activation.

209 Complement- and EGF + ionomycin-stimulated iPLA(2)gamma activity was attenuated by the S511A/S515A

210 iPLA(2)gamma activity was monitored by quantifying prost

211 In COS-1 cells that overexpress iPLA(2)gamma and cyclooxygenase-1, PGE(2) production was

212 Collectively, these results identify iPLA(2)gamma as an important mechanistic component of th

213 Collectively, these results identify iPLA(2)gamma as an obligatory upstream enzyme that is ne

214 Mice null for iPLA(2)gamma display multiple bioenergetic dysfunctional

215 Furthermore, the iPLA(2)gamma enantioselective inhibitor (R)-(E)-6-(bromo

216 Here, we utilize iPLA(2)gamma gain of function and loss of function genet

217 ioenergetics, we generated mice null for the iPLA(2)gamma gene by eliminating the active site of the

218 To identify the roles of iPLA(2)gamma in cellular bioenergetics, we generated mic

219 dels to demonstrate the robust activation of iPLA(2)gamma in murine myocardial mitochondria by Ca(2+)

220 hese results identify the obligatory role of iPLA(2)gamma in neuronal mitochondrial lipid metabolism

221 d with control cells, and was blocked by the iPLA(2)gamma inhibitor bromoenol lactone in both iPLA(2)

222 these results demonstrate that mitochondrial iPLA(2)gamma is activated by divalent cations and inhibi

223 We conclude that iPLA(2)gamma is essential for maintaining efficient bioe

224 Thus, complement-mediated activation of iPLA(2)gamma is mediated via ERK and p38 pathways, and p

225 In GECs, iPLA(2)gamma localized at the endoplasmic reticulum and

226 sm and membrane structure demonstrating that iPLA(2)gamma loss of function results in a mitochondrial

227 us mitochondrial phospholipids in transgenic iPLA(2)gamma mitochondria revealed the robust production

228 The iPLA(2)gamma pathway is cytoprotective.

229 the mechanisms by which complement activates iPLA(2)gamma provides opportunities for development of n

230 enates from transgenic myocardium expressing iPLA(2)gamma resulted in 13- and 25-fold increases in th

231 aphthalenyl)-2H-tetrahydropyran-2-one (BEL) (iPLA(2)gamma selective), but not its enantiomer, (S)-BEL

232 emia, and insulin resistance, which occur in iPLA(2)gamma(+/+) mice after high fat feeding.

233 rometry of skeletal muscle mitochondria from iPLA(2)gamma(-/-) mice demonstrated marked decreases in

234 pocyte triglyceride content was identical in iPLA(2)gamma(-/-) mice fed either a standard diet or a h

235 Respirometry of adipocyte explants from iPLA(2)gamma(-/-) mice identified increased rates of oxi

236 terations in hippocampal lipid metabolism in iPLA(2)gamma(-/-) mice including: 1) a markedly elevated

237 In contrast, mitochondria from iPLA(2)gamma(-/-) mice were insensitive to fatty acyl-Co

238 Notably, iPLA(2)gamma(-/-) mice were lean, demonstrated abdominal

239 Liver mitochondria from iPLA(2)gamma(-/-) mice were markedly resistant to calciu

240 in comparison with hepatic mitochondria from iPLA(2)gamma(-/-) mice.

241 of these findings, cytochrome c release from iPLA(2)gamma(-/-) mitochondria was dramatically decrease

242 Moreover, mitochondria from iPLA(2)gamma(-/-) mouse liver were resistant to Ca(2+)/t

243 m underlying mitochondrial uncoupling in the iPLA(2)gamma(-/-) mouse.

244 calcium-independent phospholipase A(2)gamma (iPLA(2)gamma(-/-)) are completely resistant to high fat

245 Calcium-independent phospholipase A(2)gamma (iPLA(2)gamma) (PNPLA8) is the predominant phospholipase

246 calcium-independent phospholipase A(2)gamma (iPLA(2)gamma) is a critical mechanistic participant in t

247 calcium-independent phospholipase A(2)gamma (iPLA(2)gamma) results in profound alterations in hippoca

248 calcium-independent phospholipase A(2)gamma (iPLA(2)gamma), and mitogen-activated protein kinases (MA

249 alcium-independent phospholipase A(2) gamma (iPLA(2)gamma), which possesses dual mitochondrial and pe

250 GE(2) was amplified in GECs that overexpress iPLA(2)gamma, compared with control cells, and was block

251 In GECs that overexpress iPLA(2)gamma, complement-mediated PGE(2) production was

252 d genetic inhibition of iPLA(2)beta, but not iPLA(2)gamma, diminishes diabetes-associated vascular sm

253 (2)gamma inhibitor bromoenol lactone in both iPLA(2)gamma-overexpressing and control GECs.

254 e in the catalytic activity and signaling of iPLA(2)gamma.

255 ablated by (R)-BEL or by genetic ablation of iPLA(2)gamma.

256 e major intracellular PLA2s, cPLA2alpha, and iPLA2, generate arachidonic acid and lysophosphatic acid

257 D) simulations to build structural models of iPLA(2) in association with a phospholipid bilayer.

258 This study provides evidence for the role of iPLA(2) in enhanced superoxide generation in neutrophils

259 uterium exchange experiments with the GVIA-2 iPLA(2) in the presence of both phospholipid substrate a

260 F) and calcium-independent phospholipase A2 (iPLA2) in activation of Ca2+ release-activated Ca2+ (CRA

261 6a and calcium-independent phospholipase A2 (iPLA2) in Golgi enzyme recycling, and show that retrogra

262 Expression of iPLA2 in INS-1 cells prevented the loss of mitochondrial

263 in Chagas' disease and a known activator of iPLA2, increased AA and PGE2 release, accompanied by pla

264 se-3 inhibitor blocks cleavage of endogenous iPLA(2) induced by laminin-10/11.

265 Small interfering RNA knockdown of iPLA(2) inhibited superoxide generation by neutrophils.

266 responses to menthol were less sensitive to iPLA2 inhibition.

267 nts' lymphoblasts in tissue culture with the iPLA(2) inhibitor, bromoenol lactone, partially restores

268 Another iPLA(2) inhibitor, FKGK11, also inhibited tumor developm

269 trophils with the Ca(2+)-independent PLA(2) (iPLA(2)) inhibitor bromoenol lactone (BEL) completely su

270 Hence, we propose that iPLA(2) is a potential effective and novel target for EO

271 Whereas the action of iPLA2 is immediate, the action of cPLA2 requires a lag t

272 Together, our data indicate that iPLA2 is important for the protection of mitochondrial f

273 VI Ca(2)(+)-independent phospholipase A(2) (iPLA(2)) is a water-soluble enzyme that is active when a

274 a(2+)-independent phospholipase A(2) (GVIA-2 iPLA(2)) is composed of seven consecutive N-terminal ank

275 that calcium-independent phospholipase A(2) (iPLA(2)) is involved in epithelial ovarian cancer (EOC).

276 2g5, 12a, and 12b), cPLA2 isoform (pla2g4a), iPLA2 isoform (pla2g6), and PLA2-receptor (pla2r1) were

277 iPLA2 localized to mitochondria even before apoptotic in

278 In future studies, the proposed iPLA(2) models should provide a structural basis for und

279 l information is currently available for the iPLA(2) or its membrane complex.

280 ate whether group VIA Ca2+-independent PLA2 (iPLA2) plays a role in the protection of mitochondrial f

281 Calcium-independent phospholipase A(2) (iPLA(2)) plays a pivotal role in phospholipid remodeling

282 ore calcium-independent phospholipases A(2) (iPLA(2)s) participate in the regulation of vascular tone

283 ensively examined through utilization of the iPLA2-selective inhibitor (E)-6-(bromomethylene)-3-(1-na

284 he precise binding mode of FK ligands to the iPLA(2) should greatly improve our ability to design new

285 enol lactone (BEL), a selective inhibitor of iPLA(2), significantly inhibited EOC metastatic tumor gr

286 onsensus motif common to members of the GVIA-iPLA(2) subfamily.

287 ular, the Group VIA phospholipase A(2) (GVIA-iPLA(2)) subfamily of enzymes functions independently of

288 of Asp(513) (a cleavage site of caspase-3 in iPLA(2)) to Ala blocks laminin-10/11-induced cleavage an

289 we found that STS down-regulated endogenous iPLA2 transcription in both INS-1 and iPLA2-expressing I

290 ages (BMDMs) expressed cPLA2-IVA, cPLA2-IVB, iPLA2-VI, sPLA2-IIE, and sPLA2-XIIA.

291 pathogenesis of Barth syndrome and identify iPLA2-VIA as an important enzyme in cardiolipin deacylat

292 hough in wild-type flies inactivation of the iPLA2-VIA does not affect the molecular composition of c

293 Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial ab

294 tor abnormalities seen in aged flies lacking iPLA2-VIA gene function, and restore mitochondrial membr

295 Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid pe

296 Furthermore we show that the iPLA2-VIA knockout fly model provides a useful platform

297 the Drosophila homologue of the PLA2G6 gene, iPLA2-VIA, results in reduced survival, locomotor defici

298 ng a calcium-independent phospholipase A(2), iPLA2-VIA, which also prevents cardiolipin depletion/mon

299 Models for iPLA(2) were built by homology with the known structure

300 ced cleavage and activation of overexpressed iPLA(2), whereas mutation of Asp(733) to Ala has no such

301 her keto-1,2,4-oxadiazole inhibitor for GVIA iPLA2, which will serve as lead compounds for future dev