ライフサイエンスコーパス: c-FLIP

1 c-FLIP (cellular FLICE inhibitory protein) is an enzymat

2 c-FLIP can inhibit death receptor-mediated apoptosis by

3 c-FLIP has been postulated to prevent formation of the c

4 c-FLIP inhibits caspase 8 activation and apoptosis media

5 c-FLIP is a critical regulator of the TNF family of cyto

6 c-FLIP is a TNF-alpha-induced gene that inhibits caspase

7 c-FLIP may inhibit or promote T cell death as previous d

8 c-FLIP protein levels are regulated by ubiquitination an

9 c-FLIP silencing with anti-FLIP short interfering RNA (s

10 c-FLIP(f/f) LysM-Cre mice exhibit delayed clearance of c

11 c-FLIP(L) and RIP1 also coimmunoprecipitate with active

12 c-FLIP(L) is thus not only an inhibitor of cell death by

13 c-FLIP(L) itself is a substrate of the caspase activity

14 c-FLIP(L)(-/-) mice exhibit severely impaired effector T

15 c-FLIP(L)-Tg CD8(+) T cells have increased proliferation

16 c-FLIP(L)-Tg CD8(+) T cells manifest greater caspase act

17 c-FLIP(S) and viral FLIP expression rescued E1A-mediated

18 TRAF-1, c-FLIP, and to a lesser extent c-IAP2 protein levels wer

19 of this, siRNA specifically targeted against c-FLIP(L) synergistically enhanced chemotherapy-induced

20 Although c-FLIP has been identified as an important player in the

21 Moreover, although c-FLIP has been implicated in T cell receptor signaling

22 aximal recruitment of FADD, caspase-8/10 and c-FLIP occurring when the receptor has reached an endoso

23 kinase activity or expression of PEA-15 and c-FLIP is inhibited; the results suggest that CaMKII-med

24 Sle1 expressed increased levels of Bcl-2 and c-FLIP and decreased levels of Fas RNA compared with HKI

25 are differentially regulated by cIAP1/2 and c-FLIP.

26 lated antiapoptotic genes bfl-1, cIAP-2, and c-FLIP.

27 that after T cell activation, caspase-8 and c-FLIP(L) associate in a complex enriched for active cas

28 ecruitment of endogenous FADD, caspase-8 and c-FLIP(L) but not c-FLIP(S).

29 mall portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they asso

30 Both caspase-8 and c-FLIP(L) were cleaved to form two stable intermediates

31 d positive cross-talk exists between Akt and c-FLIP in the context of inhibition of FasL-induced NF-k

32 blocked by the caspase-8 inhibitors CrmA and c-FLIP but not by Bcl-2.

33 nt Jurkat cells, we demonstrate that DR5 and c-FLIP(L) interact in a FADD-independent manner.

34 on of DISC-associated proteins, CD95/FAS and c-FLIP were commonly expressed, in 23 (92%) of 25 and 21

35 on of both c-FLIP splice forms c-FLIP(L) and c-FLIP(S) with siRNA synergistically enhanced chemothera

36 A and decreased expression of c-FLIP-(L) and c-FLIP-(S), proteins previously implicated in the modula

37 defined that expression levels of Notch3 and c-FLIP are coordinately up-regulated within the neointim

38 , indicating that both DR5 up-regulation and c-FLIP reduction contribute to cooperative induction of

39 These studies indicate that RIP and c-FLIP-mediated assembly of the DISC in nonrafts is a cr

40 Listeria monocytogenes infection in vivo and c-FLIP(L)-deficient T cells display defective TCR-mediat

41 sive anti-apoptotic genes such as Bcl-xL and c-FLIP.

42 th PVR, mediated by survival factors such as c-FLIP and c-IAP1, may help to explain unwanted and unch

43 inase inhibitors was sufficient to attenuate c-FLIP levels.

44 BV-induced genes included pleckstrin, Jun-B, c-FLIP, CIP4, and I kappa B epsilon.

45 d survivin in mediating these events because c-FLIP (i.e., FLIP(S)) and survivin protein levels were

46 r and that gamma-secretase inhibitor blocked c-FLIP turnover and also partially blocked PS1-induced a

47 Simultaneous downregulation of both c-FLIP splice forms c-FLIP(L) and c-FLIP(S) with siRNA s

48 Simultaneous ablation of both c-FLIP variants augments death receptor-mediated apoptos

49 SC assembly and activation are controlled by c-FLIP isoforms, which function as pro-apoptotic (c-FLIP

50 8 blocked the enhanced apoptosis induced by c-FLIP-targeted (FT) siRNA and chemotherapy.

51 activation is secondary, is not inhibited by c-FLIP, and is not essential for cell death.

52 2L/TRAIL can be restored at least in part by c-FLIP pathway inhibitors.

53 The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) a

54 tivation of caspase-8, which in turn cleaves c-FLIP(L) to allow RIP1 recruitment and NF-kappaB activa

55 the granulocytic subset, requires continuous c-FLIP expression to prevent caspase-8-dependent, RIPK3-

56 We found that celecoxib controlled c-FLIP ubiquitination through Akt-independent inhibition

57 initiator caspase activation and cell death, c-FLIP(L) is also capable of enhancing procaspase-8 acti

58 signaling (including coreceptor) determines c-FLIP levels and protection from CD95-induced death.

59 This is not due to direct c-FLIP phosphorylation but depends on JNK-mediated phosp

60 Furthermore, E1A expression downregulated c-FLIP(S) expression and prevented its induction by TNF-

61 els of other related proteins including DR4, c-FLIP, FADD, and caspase-8.

62 Since elevated c-FLIP levels confer resistance to apoptosis and promote

63 se-8 activation is not blocked by endogenous c-FLIP.

64 A decrease in endogenous c-FLIP by specific small interfering RNA induced TNF-alp

65 However, inhibition of endogenous c-FLIP expression by specific c-FLIP siRNA in Karpas 299

66 emonstrate that acute deletion of endogenous c-FLIP in murine effector T cells results in loss of cas

67 Thus, endogenous c-FLIP(L) functions primarily as an inhibitor of death r

68 tween NF-kappaB and PI3K/Akt and establishes c-FLIP as an important regulator of FasL-mediated cell d

69 cking CD95 expression or in cells expressing c-FLIP-s, the lethality of sorafenib + HDACI exposure wa

70 nsfectant of the KM12L4 cell line expressing c-FLIP supports the role of TRAIL and the cell-surface d

71 receptor-mediated apoptosis, by facilitating c-FLIP degradation through a ubiquitin/proteasome-depend

72 sed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1.

73 Similarly, full-length c-FLIP (c-FLIP(L)) and the C-terminal p12 domain of c-FLIP inter

74 Although the long isoform of cellular FLIP (c-FLIP(L)) has been implicated in TCR-mediated signaling

75 d not affect CD95 levels, but cellular FLIP (c-FLIP) protein and mRNA levels were reduced 2-fold comp

76 protein (c-FLIP(S)) and a long, 55-kDa form (c-FLIP(L)).

77 Cellular FLIP long form (c-FLIP(L)) is a caspase-defective homologue of caspase-8

78 Cellular FLIP long form (c-FLIP(L)) was originally identified as an inhibitor of

79 for this process is cellular FLIP long form (c-FLIP(L)), because it can block caspase-8 recruitment a

80 rting enzyme inhibitory protein, short form (c-FLIP-s) blocked enhanced killing.

81 s downregulation of both c-FLIP splice forms c-FLIP(L) and c-FLIP(S) with siRNA synergistically enhan

82 T cells from c-FLIP(L)-transgenic (Tg) mice manifest hyperproliferati

83 y we show that activated CD4(+) T cells from c-FLIP(L)-transgenic mice produce increased amounts of T

84 hyperproliferative capacity of T cells from c-FLIP(L)-transgenic mice.

85 ession of endogenous NF-kappaB target genes (c-FLIP, TRAF1), and resistance to apoptosis.

86 al role of c-FLIPL and crucially defines how c-FLIP isoforms differentially control cell fate.

87 However, c-FLIP(L)(-/-) T cells exhibit normal NF-kappaB activity

88 lpha-induced TRAF-1, TRAF-2, c-IAP1, c-IAP2, c-FLIP, and A1 gene expression and downregulated TRAF-1

89 xpression of TRAF-1, TRAF-2, c-IAP1, c-IAP2, c-FLIP, and A1.

90 ed by the caspase-8-specific inhibitor IETD, c-FLIP expression and in caspase-8-deficient cancer cell

91 m-deletion rescued the enhanced apoptosis in c-FLIP-deficient T cells, whereas inhibition of caspase

92 pathways, activation of NF-kappaB and Erk in c-FLIP-deficient thymocytes appears largely intact.

93 oxygen species (ROS) has been implicated in c-FLIP protein degradation.

94 The impaired T lymphocyte maturation in c-FLIP conditional knockout mice occurs at the single-po

95 is or increase in reactive oxygen species in c-FLIP-deficient resting T cells.

96 ulation of antiapoptotic proteins, including c-FLIP, MCL-1, and BCL-2.

97 the effects of GSK3 inhibition and increased c-FLIP ubiquitination, confirming that c-FLIP attenuatio

98 subpopulation of PC3) cells showed increased c-FLIP(L) mRNA levels and maintained steady protein expr

99 ated apoptosis in association with increased c-FLIP levels.

100 depletion of TRAF7 correlates with increased c-FLIP(L) expression level, which, in turn, results in r

101 mutant I kappa B abolished TNF-alpha-induced c-FLIP induction in RPE cells.

102 reated with the intrinsic apoptosis inducer, c-FLIP suppressed cytochrome c release from mitochondria

103 lls from these mice do not display inducible c-FLIP(L) ubiquitination and degradation.

104 Chemotherapeutic agents inhibit c-FLIP expression, thereby enhancing the DISC assembly i

105 Strategies to activate c-Fos or inhibit c-FLIP(L) may potentiate TRAIL-based proapoptotic therap

106 e repression of cellular caspase-8 inhibitor c-FLIP (also known as CFLAR) expression through activati

107 pression of high levels of the Fas inhibitor c-FLIP.

108 eliminating endogenous caspase-8 inhibitor, c-FLIP, while Smac mimetic does so by triggering autodeg

109 Thus, not only is c-FLIP the initiator of caspase-8 activity during T cell

110 lular-FLICE-inhibitory protein long isoform [c-FLIP(L)] is necessary and sufficient to maintain resis

111 Mice conditionally lacking c-FLIP in T lymphocytes display severe defects in the de

112 l knockout mouse strain specifically lacking c-FLIP(L) in T lymphocytes.

113 Similarly, full-length c-FLIP (c-FLIP(L)) and the C-terminal p12 domain of c-FL

114 e efficiently recruits RIP1 than full-length c-FLIP(L) to activate NF-kappaB.

115 nine sulfoximine down-regulates c-FLIP long (c-FLIP(L)) protein levels, which is prevented by the pro

116 that persistent expression of c-FLIP(Long) [c-FLIP(L)] is inversely correlated with the ability of T

117 Two major c-FLIP variants result from alternative mRNA splicing: a

118 ain were found to be important for mediating c-FLIP-dependent downregulation of NF-kappaB activity.

119 in turn, repress the antiapoptotic molecule c-FLIP(L).

120 ent by repressing the antiapoptotic molecule c-FLIP(L).

121 nd markedly decreasing the survival molecule c-FLIP (cellular homolog of viral FLICE inhibitory prote

122 Furthermore, the expression of Mcl-1 but not c-FLIP was significantly reduced when COX-2 was suppress

123 ermore, overexpression of c-FLIP(L), but not c-FLIP(S), potently inhibited apoptosis induced by chemo

124 genous FADD, caspase-8 and c-FLIP(L) but not c-FLIP(S).

125 to involve cytokine-induced acceleration of c-FLIP degradation, sensitizing cells to TRAIL-mediated

126 vide molecular insights into a key aspect of c-FLIP(L) function that modulates procaspase-8 activatio

127 on after TCR ligation via the association of c-FLIP(L) with Raf-1.

128 with GSK3 inhibition enhanced attenuation of c-FLIP and increased apoptosis.

129 The Th2 bias of c-FLIP(L)-transgenic CD4(+) T cells parallels impaired N

130 The Th2 bias of c-FLIP(L)-transgenic mice extends to an enhanced sensiti

131 lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site.

132 -FLIP(L) and demonstrate that degradation of c-FLIP(L) also occurs through a lysosomal pathway.

133 ion- and proteasome-dependent degradation of c-FLIP(S) protein.

134 is, but the impact of selective depletion of c-FLIP(L) on caspase-8 activation and subsequent apoptos

135 e corresponding to the DR5 binding domain of c-FLIP induces apoptosis in mammalian cells.

136 (c-FLIP(L)) and the C-terminal p12 domain of c-FLIP interacted with DR5 both in in vitro pull-down as

137 al structures of the protease-like domain of c-FLIP(L) alone and in complex with zymogen C8 identify

138 he presence of two death effector domains of c-FLIP and S-nitrosylation of its caspase-like domain we

139 We observed dysregulation of c-FLIP by IL-2 in leukemic LGL, suggesting a role in Fas

140 We studied the effect of c-FLIP on the apoptotic response to chemotherapies used

141 We have further explored the effect of c-FLIP(L) on CD8(+) effector T cell function and its mec

142 nism through which the regulatory effects of c-FLIP on death receptor signaling are controlled by GSK

143 by promoting the proteasomal elimination of c-FLIP(L).

144 ide but not LY294002 decreases expression of c-FLIP (cellular FLICE inhibitory protein), an inhibitor

145 reatment resulted in decreased expression of c-FLIP and Mcl-1, which were determined to be transcript

146 It is noteworthy that enforced expression of c-FLIP or silencing of DR5 expression using DR5 small in

147 Accordingly, expression of c-FLIP T166A or K167R mutants protected cells from ROS-m

148 and maintained steady protein expression of c-FLIP(L) after treatment with TRAIL.

149 s that specifically knock down expression of c-FLIP(L) in several cancer cell lines and studied their

150 The expression of c-FLIP(L) in T cells can also augment extracellular sign

151 Ectopic expression of c-FLIP(L) in TRAIL-sensitive PC3 cells changed their phe

152 Therefore, persistent expression of c-FLIP(L) is necessary and sufficient to regulate sensit

153 Increased expression of c-FLIP(L) results in augmented caspase activity in resti

154 Here, we show that persistent expression of c-FLIP(Long) [c-FLIP(L)] is inversely correlated with th

155 Of these, two reduced expression of c-FLIP, an intracellular antagonist of the extrinsic pat

156 eceptor and PUMA and decreased expression of c-FLIP-(L) and c-FLIP-(S), proteins previously implicate

157 Treatment with BBR3610 reduced expression of c-FLIP-s and MCL-1, levels that were maintained in cells

158 2 reduced the abundance of the short form of c-FLIP (FLIP(S), CFLAR(S)) and survivin (BIRC5).

159 To investigate the function of c-FLIP in mature T cells, we have generated several gene

160 s well established; however, the function of c-FLIP(L) remains controversial.

161 not clear which of the various functions of c-FLIP(L) was involved.

162 Subsequently, additional functions of c-FLIP(L) were identified through its association with r

163 A inhibited TNF-alpha-dependent induction of c-FLIP(S) mRNA and stimulated ubiquitination- and protea

164 Inhibition of c-FLIP by means of RNA interference increased Apo2/TRAIL

165 e ubiquitously expressed, the interaction of c-FLIP(L) and DR5 indicates a mechanism by which tumor s

166 We exclude the involvement of c-FLIP and survivin in mediating these events because c-

167 Short hairpin RNA-mediated knockdown of c-FLIP or Mcl-1 significantly sensitized these cells to

168 Knockdown of c-FLIP(L) augmented DISC recruitment, activation, proces

169 eukemia patients express increased levels of c-FLIP and display resistance to Fas-mediated apoptosis

170 t not Treg cells because of higher levels of c-FLIP expression in Treg cells.

171 y also underscore the view that as levels of c-FLIP increase, Fas signaling can be diverted from indu

172 nt with ABT-737 did not change the levels of c-FLIP, FADD, and caspase-8 but up-regulated the levels

173 and SU-DHL1, each expressing high levels of c-FLIP.

174 that cleavage of the intersubunit linker of c-FLIP(L) by procaspase-8 potentiates the activation pro

175 avenger prevented ubiquitination and loss of c-FLIP(L) protein induced by menadione or paraquat.

176 iated death domain and caspase-8, but not of c-FLIP, into the Apo-2L/TRAIL-induced death-inducing sig

177 ation of NF-kappaB through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respective

178 Our findings suggest that overexpression of c-FLIP protects ALK+ ALCL cells from death-receptor-indu

179 ies have demonstrated that overexpression of c-FLIP(L) promotes T cell proliferation and NF-kappaB ac

180 Furthermore, overexpression of c-FLIP(L), but not c-FLIP(S), potently inhibited apoptos

181 Overexpression of c-FLIP, particularly FLIP(L), inhibited not only celecox

182 Overexpression of c-FLIP-s or loss of BID function suppressed BBR3610 toxi

183 Reduction of c-FLIP with c-FLIP siRNA sensitized cells to PS-341-indu

184 e-mediated apoptosis, while up-regulation of c-FLIP by gene transfer partially protected dermal MVECs

185 Moreover, down-regulation of c-FLIP using small interfering RNA in nonactivated T cel

186 ed ATL by transcriptional down-regulation of c-FLIP, a key inhibitor of death receptor signaling, and

187 ivity in association with down-regulation of c-FLIP, suggesting that c-FLIP synthesis, not intracellu

188 via induction of DR5 and down-regulation of c-FLIP.

189 n of death receptor 5 and down-regulation of c-FLIP.

190 t this may be mediated by down-regulation of c-FLIP.

191 Therefore, c-Fos is a key regulator of c-FLIP(L), and activation of c-Fos determines whether a

192 y, our data suggest that the primary role of c-FLIP in thymocyte maturation is to protect cells from

193 ture T lymphocytes in vitro, and the role of c-FLIP protein in intrinsic apoptosis pathway was studie

194 To establish the role of c-FLIP(L) in T lymphocyte proliferation, we have generat

195 The role of c-FLIP(S) as an inhibitor of death receptor-mediated apo

196 Conversely, silencing of c-FLIP(L) expression by small interfering RNA in PC3-TR

197 lysine 167 as a novel ubiquitination site of c-FLIP(L) important for ROS-dependent degradation.

198 stretch of amino acids in the C terminus of c-FLIP(L).

199 rizes with c-Jun to repress transcription of c-FLIP(L).

200 se-dependent pathway mediated by turnover of c-FLIP and the gamma-secretase-independent pathway media

201 f this protein in regulating the turnover of c-FLIP and, consequently, cell death.

202 onectin, soluble factor(s) have no impact on c-FLIP redistribution within cellular compartments.

203 n contrast, inhibition of CaMKII, PEA-15, or c-FLIP does not affect the sensitivity of human astrocyt

204 d substrate repertoire, limited to itself or c-FLIP.

205 Inhibition of PEA-15/PED or c-FLIP by small interfering RNA sensitizes human astrocy

206 sistance and thus targeting of either RIP or c-FLIP may lead to the development of novel therapeutic

207 fts and selective knockdown of either RIP or c-FLIP with interfering RNA redistributes the DISC from

208 The caspase-8 paralogue c-FLIP is a good candidate for a molecular rheostat of c

209 1 that fail to activate caspase-8 and permit c-FLIP(L) cleavage cannot facilitate NF-kappaB activatio

210 ver, reductions in the antiapoptotic protein c-FLIP in response to PS-341 were observed in both C1498

211 O-Im down-regulate the antiapoptotic protein c-FLIP(L), and up-regulate cell surface TRAIL receptors

212 the NF-kappaB-induced antiapoptotic protein c-FLIP, an inhibitor of caspase-8.

213 aseline levels of the anti-apoptotic protein c-FLIP in all cell lines tested.

214 ubiquitination of the anti-apoptotic protein c-FLIP(L) and demonstrate that degradation of c-FLIP(L)

215 The cytosolic protein c-FLIP (cellular Fas-associated death domain-like interl

216 aspases-8 and -10 and the regulatory protein c-FLIP.

217 Cellular FLICE-inhibitory protein (c-FLIP(L)) is a key regulator of the extrinsic cell deat

218 levels of cellular FLICE-inhibitory protein (c-FLIP) (both the long and short forms), key inhibitors

219 n of cellular FLICE-like inhibitory protein (c-FLIP) and Mcl-1.

220 apoptosis regulator-like inhibitory protein (c-FLIP) and myeloid cell leukemia 1 (Mcl-1).

221 a-converting enzyme-like inhibitory protein (c-FLIP) expression was determined by Western blot.

222 FLICE inhibitory protein (c-FLIP) is an important regulator of TRAIL-induced apopt

223 r caspase 8 (FLICE)-like inhibitory protein (c-FLIP) is required for TNFalpha-induced protection agai

224 is pathway by FLICE-like inhibitory protein (c-FLIP) may contribute to oncogenesis in ALK+ anaplastic

225 -1beta-converting enzyme-inhibitory protein (c-FLIP) mediates the DISC assembly in nonrafts and selec

226 r caspase 8 (FLICE)-like inhibitory protein (c-FLIP) promotes cell survival in death receptor-induced

227 nism by which FLICE-like inhibitory protein (c-FLIP) regulates apoptosis induced by tumor necrosis fa

228 with cellular FLICE-like inhibitory protein (c-FLIP) turnover and that gamma-secretase inhibitor bloc

229 ession of cellular FLICE-inhibitory protein (c-FLIP), a major negative regulator of the death recepto

230 dation of cellular FLICE-inhibitory protein (c-FLIP), a major regulator of the death receptor pathway

231 that cellular FLICE-like inhibitory protein (c-FLIP), a procaspase-8-like apoptotic regulator, plays

232 Cellular FLICE-inhibitory protein (c-FLIP), an antioxidant and an important component of th

233 lation of cellular FLICE inhibitory protein (c-FLIP), an inhibitor of apoptosis.

234 ator cellular FLICE-like inhibitory protein (c-FLIP), targeting it for proteasome degradation.

235 -1beta-converting enzyme-inhibitory protein (c-FLIP), thus releasing their inhibition of caspase-8 cl

236 a-converting enzyme-like inhibitory protein (c-FLIP), were expressed in basal conditions in both cult

237 1beta-converting enzyme inhibitory protein (c-FLIP), whose expression was coregulated by VEGF and PE

238 -converting enzyme)-like inhibitory protein (c-FLIP).

239 levels of cellular FLICE-inhibitory protein (c-FLIP).

240 crease in cellular FLICE-inhibitory protein (c-FLIP).

241 lation of cellular FLICE-inhibitory protein (c-FLIP, I-FLICE) without evidence of Fas (CD95) up-regul

242 n of cellular FLICE-like inhibitory protein (c-FLIP-s) or knockdown of CD95 suppressed the lethality

243 n of cellular FLICE-like inhibitory protein (c-FLIP-s).

244 tive mRNA splicing: a short, 26-kDa protein (c-FLIP(S)) and a long, 55-kDa form (c-FLIP(L)).

245 se APL cells, in which PMLRARalpha recruited c-FLIP(L/S) and excluded procaspase 8 from Fas death sig

246 cause TGM2 suppression significantly reduced c-FLIP but not Mcl-1 expression.

247 es its transcriptional activity, and reduces c-FLIP(L) mRNA and protein levels.

248 tment caused DISC formation without reducing c-FLIP-s expression and did not increase CD95 plasma mem

249 essential for soluble factor(s) to regulate c-FLIP.

250 by which ROS post-transcriptionally regulate c-FLIP protein levels is not well understood.

251 at, or buthionine sulfoximine down-regulates c-FLIP long (c-FLIP(L)) protein levels, which is prevent

252 is activated by MG-132, negatively regulates c-FLIP(L) by direct binding to the putative promoter reg

253 than hen egg lysozyme alone in up-regulating c-FLIP levels and for protection against CD95-mediated a

254 To the contrary, TRAIL treatment released c-FLIP(L) from DR5, permitting the recruitment of FADD t

255 ancer cells by inducing c-Fos and repressing c-FLIP(L).

256 of endogenous c-FLIP expression by specific c-FLIP siRNA in Karpas 299 and SU-DHL1 cells treated wit

257 r-166 or Lys-167 was sufficient to stabilize c-FLIP protein levels in PPC-1, HEK293T, and HeLa cancer

258 In this study, c-FLIP gene was deleted in mature T lymphocytes in vitro

259 cleavage of two known caspase-8 substrates, c-FLIP(L) and receptor interacting protein 1.

260 ted in cleavage of the caspase-8 substrates, c-FLIP(L), receptor interacting protein 1, and to a less

261 poptotic pathway is inhibited by a sustained c-FLIP expression associated with the expression of HCV

262 sing therapeutic potential, act by targeting c-FLIP ubiquitination and degradation by the proteasome.

263 Moreover, targeting c-FLIP in combination with existing chemotherapies may h

264 Current models assume that c-FLIP directly competes with procaspase-8 for recruitme

265 eased c-FLIP ubiquitination, confirming that c-FLIP attenuation was mediated by proteasomal turnover

266 Our results demonstrate that c-FLIP functions beyond the extrinsic death pathway.

267 These results demonstrate that c-FLIP(L) is essential for T lymphocyte proliferation th

268 Surprisingly, we found that c-FLIP protects mature T cells not only from apoptosis i

269 We have found that c-FLIP(L) is transcriptionally regulated by the activato

270 These results thus indicate that c-FLIP down-regulation also contributes to celecoxib-ind

271 These results indicate that c-FLIP inhibits TRAIL-independent, DR5- and caspase 8-de

272 Taken together, these findings indicate that c-FLIP interacts with the DD of DR5, thus preventing dea

273 ctivation, whereas others have reported that c-FLIP(L) overexpression has no effect or even inhibits

274 Taken together, these results show that c-FLIP(L) can influence cytokine gene expression to prom

275 Subsequent studies showed that c-FLIP was degraded, that caspase-8 was activated, and t

276 These data suggest that c-FLIP is a negative regulator of intrinsic apoptosis pa

277 to PS-341-induced apoptosis, suggesting that c-FLIP elevation protects cells from PS-341-induced apop

278 h down-regulation of c-FLIP, suggesting that c-FLIP synthesis, not intracellular traffic, is essentia

279 apy in HCT116p53(+/+) cells, suggesting that c-FLIP(L) was the more important splice form in mediatin

280 Although the c-FLIP(R) isoform inhibits cell death in cell lines, its

281 c-Fos binds the c-FLIP(L) promoter, represses its transcriptional activi

282 Interestingly, the c-FLIP(short) was detected only in TCR-ligated Siva-1 kn

283 dent post-translational modifications of the c-FLIP protein that regulate its stability, thus impacti

284 nding to the putative promoter region of the c-FLIP(L) gene.

285 death as previous data demonstrate that the c-FLIP(L) isoform can promote or inhibit caspase 8 activ

286 -dependent increase of NFATc2 binding to the c-FLIP promoter in vivo, which was attenuated by PEDF.

287 te or inhibit caspase 8 activation while the c-FLIP(S) isoform promotes or inhibits T cell death when

288 -mediated TRAIL resistance is likely through c-FLIP because TGM2 suppression significantly reduced c-

289 Thus, c-FLIP plays an essential role in protecting mature T ce

290 s not alter the activity of caspase-8 toward c-FLIP(L), which is required for antigenic signaling.

291 Although overexpression of transfected c-FLIP(L) inhibits apoptosis, ectopic expression at lowe

292 T cells from cellular FLIP long transgenic (c-FLIP(L)-Tg) mice that manifest elevated caspase activi

293 igase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation.

294 lation of the endothelial cell apoptosis via c-FLIP controlled by NFAT and its upstream regulator JNK

295 Whether c-FLIP regulates mitochondrion-dependent apoptotic signa

296 Thus, one mechanism by which c-FLIP(L) influences effector T cell function is through

297 forming an apoptotic inhibitory complex with c-FLIP.

298 Reduction of c-FLIP with c-FLIP siRNA sensitized cells to PS-341-induced apoptosi

299 generated several genetic mouse models with c-FLIP or its individual isoforms deleted in mature T ce

300 h as X-linked inhibitor of apoptosis (XIAP), c-FLIP long, and Bcl-x(L) that were accompanied with mit