ライフサイエンスコーパス: TSC1

1 e negative regulators, tuberous sclerosis 1 (Tsc1).

2 mor suppressor tuberous sclerosis complex 1 (TSC1).

3 established BCa genes (TP53, RB1, CDKN2A and TSC1).

4 with conditional alleles of each of Tp53 and Tsc1.

5 in 1 (Hap1) as a novel functional partner of Tsc1.

6 ns in the network increases with the loss of Tsc1.

7 unction downstream of the canonical PI3K/AKT/TSC1-2 pathway.

8 However, the relationship between TSC1/2 and HIF1a and the function of HIF1a in TSC neuron

9 thelial phenotype of TSC astrocytes suggests TSC1/2 and mTOR tune the phosphorylation level of cateni

10 Our data suggest targeting TSC1/2 as a strategy for boosting antitumor immune thera

11 ogether, our findings indicate that neuronal Tsc1/2 complex activity is required for the coordinated

12 d alphaB-crystallin has an essential role in TSC1/2 complex deficiency-mediated tumorigenesis, and in

13 nd requires the Ssp2 (AMPKalpha) kinase, the Tsc1/2 complex, and Rhb1 GTPase.

14 ortant role in health and aging, the role of TSC1/2 in aging has not been fully investigated.

15 TSC1/2 negatively regulate the function of mTOR, which i

16 In this study, we demonstrate that neuronal TSC1/2 orchestrates a program of oligodendrocyte maturat

17 TSC1/2 protein complex negatively regulates the mammalia

18 nents (for example, PTEN loss, PIK3CA, AKT1, TSC1/2) are common in bladder cancer, yet small-molecule

19 tivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC), a hereditary syn

20 The tuberous sclerosis complex 1/2 (TSC1/2) is an endogenous regulator of the mechanistic ta

21 Tuberous sclerosis complex-1 or 2 (TSC1/2) mutations cause white matter abnormalities, incl

22 gets, including Akt, PKCzeta, AMPKalpha-LKB1-TSC1/2, and their association with BVRA.

23 inactivating mutations in the genes encoding TSC1/2, negative regulators of the mammalian target of r

24 tively feed back to mTORC1 through an AMPK-, TSC1/2-, and Rag-independent mechanism by regulating mTO

25 Surprisingly, unlike AMPK-, Lkb1- or Tsc1/2-deficient cells, FoxO-deficient cells exhibit dec

26 vel, high mTORC1-driven translation rates in TSC1/2-deficient cells, unlike wild-type cells, sensitiz

27 that the UPR could be targeted to eradicate TSC1/2-null cells during patient therapy.

28 /B GTPases and for RalGAPalpha/beta, but not Tsc1/2.

29 isposition syndrome) cascade upstream of the TSC1/2/mTOR pathway and thus likely to be a tumor suppre

30 The C-terminal domain of Tsc1 (998-1,164 aa) forms a homodimer and binds to both

31 in this study that the tuberous sclerosis 1 (TSC1), a negative regulator of mTOR signaling, plays a c

32 We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial ro

33 Surprisingly, targeted mutation of Tsc1, a negative regulator of mTORC1, caused a broad red

34 stinct, representing the N- and C-termini of TSC1; a "pincer" is formed by the highly flexible N-term

35 Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (E

36 Collectively, these studies suggest that TSC1 acts as an important checkpoint for maintaining imm

37 oligodendrocytes, we reveal that deletion of Tsc1 affects oligodendroglia differently depending on th

38 this issue, Park et al. examine the role of TSC1, an mTOR signaling regulator, in T cell differentia

39 enic mutations in 13 patients/families (6 in TSC1 and 7 in TSC2), 5 of which were novel.

40 um homeostasis and demonstrates that loss of TSC1 and activation of mTORC1 results in dedifferentiati

41 indows in 5 genes; DNA methylation of SMAD1, TSC1 and AKT1 showed significant difference across breed

42 We show that loss of Tsc1 and constitutive activation of mTORC1 in dopamine n

43 enhanced by Treg-specific double deletion of Tsc1 and Foxo3a.

44 the metabolic effects observed upon loss of TSC1 and hyperactivation of mTORC1 in the liver.

45 onset of any strain, indicating that loss of Tsc1 and Pten have synergistic effects on tumorigenesis.

46 cell proliferation, in the renal tubules of Tsc1 and rpS6 double-mutant mice.

47 campal neurons induces the downregulation of Tsc1 and stimulates the activity of mTORC1, as reflected

48 were established, which showed loss of both Tsc1 and Tp53, with mammalian target of rapamycin comple

49 Both human TSC1 and TSC2 are important tumour suppressors, and muta

50 The tuberous sclerosis proteins TSC1 and TSC2 are key integrators of growth factor signa

51 The TSC proteins Tsc1 and Tsc2 control the mTORC1 signaling pathway in di

52 The tumor suppressors Tsc1 and Tsc2 form the tuberous sclerosis complex (TSC),

53 did not reveal any genomic rearrangements in TSC1 and TSC2 in the samples with no mutations identifie

54 r knowledge, this is the first comprehensive TSC1 and TSC2 mutational analysis carried out in TSC pat

55 complex (TSC) is caused by mutations in the TSC1 and TSC2 tumor suppressor genes.

56 LCCLs with inactivating mutations in TSC1 and TSC2 were sensitive to the mammalian target of

57 method to search for SS/L interactions with TSC1 and TSC2, the two tumor suppressors underlying tube

58 egulation of the mTORC1-inhibitory proteins, TSC1 and TSC2.

59 tation in one of two tumor suppressor genes, TSC1 and TSC2.

60 genes implicated in disease development are TSC1 and TSC2.

61 Tsc1(-/-) and Tsc2(-/-) mouse embryonic fibroblasts expr

62 Tuberous sclerosis complex 1 (TSC1) and TSC2 are suppressors of mechanistic target of

63 ase B1 (LKB1), tuberous sclerosis complex 1 (TSC1) and tuberous sclerosis complex 2 (TSC2), leads to

64 Mutations in TSC1, and possibly other genes, may predict for sensitiv

65 he biologic basis for the difference between TSC1- and TSC2-based disease is unclear.

66 LKB1 and TSC2, but not TSC1, are required for PERK-mediated inhibition of mamma

67 In this study, we identify TSC1 as a component of the transforming growth factor be

68 Our findings establish an active role for Tsc1 as a facilitator of Hsp90-mediated folding of kinas

69 Previous studies have identified Tsc1 as a regulator of hippocampal neuronal morphology a

70 We hypothesized that thalamic deletion of Tsc1 at distinct stages of mouse brain development would

71 IRI) in normal and steatotic liver using Alb-TSC1(-/-) (AT) and Alb-mTOR(-/-) (Am) transgenic mice.

72 that the TSC2 N terminus interacts with the TSC1 C terminus to mediate complex formation.

73 ia ablation of tuberous sclerosis complex 1 (TSC1), causes hypomyelination characterized by downregul

74 th collecting-duct (CD)-specific ablation of TSC1 (CDTsc1KO) had greater mTOR complex 1 (mTORC1) acti

75 t dimer, along the surface of which runs the TSC1 coiled-coil backbone, breaking the symmetry of the

76 ore domains and a barbed "tail" makes up the TSC1 coiled-coil-TBC1D7 junction.

77 ent neurons, as well as in a neuron-specific Tsc1 conditional knock-out mouse model, and show differe

78 ) structure-related gene expression, whereas Tsc1 conditional knockout mice exhibited changes in gene

79 In addition, Tsc1 conditional knockout mice presented severely disorg

80 was significantly reduced in both Raptor and Tsc1 conditional knockout mice, albeit with variations i

81 y activation are also found in the brains of Tsc1-conditional mouse models and in cortical tubers res

82 Transcriptome analysis indicated that Tsc1 coordinated gene expression programs underlying imm

83 is formed by the highly flexible N-terminal TSC1 core domains and a barbed "tail" makes up the TSC1

84 Thus, TSC1 couples Akt activity to TGF-beta-Smad2/3 signaling.

85 Activation of mTOR by leucine or deletion of TSC1 decreased expression of brown adipocyte-related gen

86 expressing a cognate antigen, we found that TSC1 deficiency impairs antigen-specific CD8 T cell resp

87 protein (THP), a loop of Henle marker, while Tsc1 deficiency in Osx lineage cells caused development

88 Tsc1 deficiency in Prx1 lineage cells caused development

89 On the other hand, Tsc1 deficiency in the Dermo1 lineage did not produce de

90 Tsc1 deficiency suppressed the generation of memory-prec

91 O targets that restrict the proliferation of Tsc1-deficient cells under nutrient restriction (NR).

92 Poor expansion of TSC1-deficient cells was associated with defects in surv

93 Mechanistically, Tsc1-deficient DCs exhibited increased glycolysis, mitoc

94 Moreover, TSC1-deficient iNKT cells display enhanced antitumor imm

95 inance of iNKT-17 cells in the population of TSC1-deficient iNKT cells.

96 d-type counterparts and antigen rechallenge, TSC1-deficient memory cells showed moderate defects in e

97 They found that enhanced mTOR activity in Tsc1-deficient T cells promotes Th1 and Th17 differentia

98 Tsc1-deficient Tregs had impaired suppressive activity i

99 rpS6 suppresses cystogenesis and fibrosis in Tsc1-deleted kidneys.

100 Tsc1 deletion at this early stage is unique in causing b

101 Both leucine and TSC1 deletion blocked nesfatin-1-induced up-regulation o

102 ssociation and Akt phosphorylation in liver, Tsc1 deletion failed to cause glucose intolerance or pro

103 Moreover, Tsc1 deletion failed to stimulate phospho-Ser-302 or oth

104 Following acute Tsc1 deletion from hepatocytes, Akt phosphorylation, but

105 Tsc1 deletion from NG2(+) OPCs accelerated remyelination

106 Conversely, Tsc1 deletion from proteolipid protein (PLP)-positive ol

107 onstitutive activation of mTOR signalling by Tsc1 deletion in the oligodendrocyte lineage results in

108 Conditional Tsc1 deletion in Tregs impaired their suppressive activi

109 during remyelination in which the timing of Tsc1 deletion is a critical determinant of its effect on

110 Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysre

111 s as a model system, we found that epidermal Tsc1 deletion resulted in a phenotype characterized by w

112 We find that neuron-specific Tsc1 deletion results in an increase in CTGF secretion t

113 Here we use cell type-specific Tsc1 deletion to test whether dopamine neurons, which mo

114 We show that mosaic Tsc1 deletion within thalamic precursors at embryonic da

115 eveloped epilepsy a few days after biallelic Tsc1 deletion.

116 complex 1 (mTORC1) activation, we find that Tsc1(Delta/Delta) macrophages are refractory to IL-4-ind

117 h myeloid lineage-specific deletion of Tsc1 (Tsc1(Delta/Delta)) leads to constitutive mTOR complex 1

118 Our data indicate that TSC1-dependent control of mTORC1 is crucial for terminal

119 Hyperactive Akt specifically activates TSC1-dependent cytostatic Smad signaling to induce growt

120 ic TGF-beta signaling by inhibiting Akt- and TSC1-dependent Smad activation.

121 nant of newborn neuron survival and that its TSC1-dependent up-regulation gave Tsc1(null) neurons a s

122 -derived NO is associated with impaired TSC2/TSC1 dimerization, mTOR pathway activation, and prolifer

123 rization of TSC2 with its inhibitory partner TSC1, enhancing GTPase activity of its target Ras homolo

124 Here, we determined that mice lacking TSC1 exhibit a developmental block of iNKT differentiati

125 data demonstrated that moderate increase of TSC1 expression can enhance overall health, particularly

126 In vivo, suppression of TSC1 expression increased locomotor activity and decreas

127 Cyst formation in Prx1-Cre; Tsc1(f/f) and Osx-Cre; Tsc1(f/f) mice were associated wi

128 ormation in Prx1-Cre; Tsc1(f/f) and Osx-Cre; Tsc1(f/f) mice were associated with increase in both pro

129 ronger effector-like phenotype compared with Tsc1-/- Foxp3+ Tregs.

130 Here, we provide evidence that deletion of Tsc1 from OPCs, but not differentiating oligodendrocytes

131 Here, TSC1 functions independently of TSC2.

132 Hyperactivation of mTORC1 via TSC1 gene deletion in chondrocytes causes uncoupling of

133 Biallelic Tsc1 gene deletion was induced in adult Tsc1 heterozygou

134 In mice with a conditionally inactivated Tsc1 gene in glia, 8 significantly reduced the loss of T

135 mice with neuronal-specific ablation of the Tsc1 gene.

136 ecific deletion of the tuberous sclerosis 1 (Tsc1) gene which encodes an upstream suppressor of mTORC

137 ly ablated the tuberous sclerosis complex 1 (Tsc1) gene, an mTOR inhibitor, in the rods of the Pde6b(

138 ogically linked to mutations in the tsc2 and tsc1 genes in the case of LAM.

139 excellent brain penetration, and efficacy in Tsc1(GFAP)CKO mice qualify 8 as a potential therapeutic

140 biallelic inactivation of either TSC genes (TSC1, hamartin or TSC2, tuberin), an event that is impli

141 Similarly, mice lacking neuronal Tsc1 have a hypomyelination phenotype.

142 transcriptional activity when compared with Tsc1 heterozygote neurons and a marked resistance to cel

143 ells (NPCs) of tuberous sclerosis complex 1 (Tsc1) heterozygote mice leads to heterotopia and abnorma

144 elic Tsc1 gene deletion was induced in adult Tsc1 heterozygous and wild-type mice.

145 channel 4 (CLIC4) and tuberous sclerosis 1 (TSC1), important innate immunity regulators.

146 Mice with specific deletion of Tsc1 in antigen-experienced CD8(+) T cells evoked normal

147 aling induced by acute biallelic deletion of Tsc1 in healthy adult mice.

148 Deficiency of TSC1 in iNKT cells results in resistance to alpha-GalCer

149 ption factor Myc, highlighting a key role of Tsc1 in modulating metabolic programming of DC different

150 le deletion system, we show that deletion of Tsc1 in mouse primary mammary tumor cells, either before

151 evealed an essential cell-intrinsic role for TSC1 in T cell survival, quiescence, and mitochondrial h

152 The loss of Tsc1 in the mouse neural tube increases the number of th

153 evidence of a CD8 T cell-intrinsic role for TSC1 in the regulation of antigen-specific primary and m

154 of the tuberous sclerosis complex protein 1 (Tsc1) in renal proximal tubules induced strikingly enlar

155 mor suppressor tuberous sclerosis complex 1 (Tsc1) in the liver promotes gluconeogenesis and glucose

156 eurons lacking tuberous sclerosis complex 1, Tsc1, in a mouse model of genetic epilepsy.

157 tive regulators of mTORC1, including TSC2 or TSC1, in developing SCs of mutant mice.

158 tudy, we examine the role of its suppressor, TSC1, in the regulation of antigen-specific primary and

159 se was characterized by loss of 9q including TSC1, increased KI67 labeling index, upregulated glycoly

160 in glia, 8 significantly reduced the loss of Tsc1-induced mortality at 50 mg/kg p.o. twice a day.

161 TSC1 interacts with the TGF-beta receptor complex and Sm

162 Here, we show that Tsc1 is a new co-chaperone for Hsp90 that inhibits its A

163 set of these phenotypes occurs when thalamic Tsc1 is deleted at a later embryonic stage.

164 Using two different mouse models in which Tsc1 is deleted by Cre expression in oligodendrocyte pro

165 henotypes also occur when only one allele of Tsc1 is deleted.

166 The tumor suppressor tuberous sclerosis 1 (TSC1) is an important negative regulator of mTOR signali

167 components led to an enhanced overgrowth of Tsc1 knockdown tissue.

168 vivo recapitulate the phenotypes induced by Tsc1 knockdown.

169 d expression of eomesodermin among activated TSC1 knockout cells.

170 capitulated in intestinal stem cell-specific Tsc1 knockout mice.

171 e performed small-RNA sequencing on liver of Tsc1-knockout mice, and found that miRNAs of the delta-l

172 L-Tsc1 KO mice displayed reduced locomotor activity, body

173 Using RVF5, we show that Tsc1 KO neurons exhibit increased activity relative to w

174 In Tsc1 KO neurons, weakened inhibition caused by deregulat

175 siology, we generated liver-specific Tsc1 (L-Tsc1 KO) knockout mice.

176 body physiology, we generated liver-specific Tsc1 (L-Tsc1 KO) knockout mice.

177 ectedly, constitutive mTORC1 activation with Tsc1 loss increased lysosomal content via upregulated ex

178 Tsc1 loss increased retinal angiogenesis in neonates and

179 Increase of ER stress in Tsc1 loss-of-function cells upon foxo knockdown was also

180 These findings establish a Tsc1-mediated checkpoint in linking immune signaling and

181 This study highlights that TSC1-mediated control of mTOR activity impinges on the b

182 cific GluN2C/D antagonists block seizures in Tsc1(+/-) mice in vivo and in vitro.

183 Here we report that tuberless heterozygote Tsc1(+/-) mice show functional upregulation of cortical

184 Thus, TSC1-mTOR signalling acts as an important checkpoint for

185 ogether, our data reveal unexpected roles of TSC1/mTOR that control multifaceted functions of DCs.

186 Our results establish a critical role for Tsc1-mTORC1 signaling in setting the functional properti

187 ficient cells, both in culture and in mosaic Tsc1 mutant mice.

188 ice recapitulate the pathologies observed in Tsc1 mutant mice.

189 flexible behaviors, respectively, in male PC-Tsc1 mutant mice.

190 le of FoxO in limiting ER stress to regulate Tsc1 mutant overgrowth.

191 d abnormally decorates the apical surface of Tsc1-mutant cells with E-cadherin and alpha-catenin.

192 ockin of a nonphosphorylatable rpS6 in these Tsc1-mutant mice exacerbated cystogenesis and caused dra

193 The concomitant loss of S6K1 in Tsc1-mutant mice restores OCD but does not decrease hype

194 nregulation by mTORC1 in the cystogenesis of Tsc1 mutants.

195 and partially rescues myelination defects in Tsc1 mutants.

196 ence of ARID1A, FGFR3, PIK3CA, STAG2, and/or TSC1 mutation and absence of TP53, RB1, or KDM6A mutatio

197 detected in 53% (10 of 19) of patients with TSC1 mutation, 65% (11 of 17) of patients with TSC2 muta

198 d that its TSC1-dependent up-regulation gave Tsc1(null) neurons a survival advantage, despite their m

199 FLNA, and decreasing MEK-ERK1/2 signaling in Tsc1(null) neurons rescued dendritic defects.

200 Surprisingly, FLNA overexpression in Tsc1(null) neurons was dependent on MEK1/2 but not mTOR

201 In Tsc1(null) neurons, knocking down FLNA in vivo prevented

202 HIF1a constructs resulted in 80-90% loss of Tsc1(null) newborn neurons although sparing SVZ stem cel

203 exosomes derived from tuberous sclerosis 1 (Tsc1)-null cells transform phenotypes of neighboring wil

204 Treatment of both Tsc2(+/) (-) mice and a TSC1-null bladder cancer xenograft model with a CDK7 inh

205 of gamma-secretase complex presenilin 1 from Tsc1-null cells to wild-type cells leading to the activa

206 ner that they become functionally similar to Tsc1-null cells.

207 on of fibroblast growth factor receptor 1 in Tsc1-null mice suppressed Akt and mitogen-activated prot

208 A fate-mapping study revealed that Tsc1-null Tregs that lost Foxp3 expression gained a stro

209 ed autophagy, was increased significantly in Tsc1-null tumor cells.

210 ey inhibitory components upstream of mTORC1, TSC1 or PTEN, in mouse SC development, adult homeostasis

211 emonstrate that reduced expression of either TSC1 or TSC2 causes reduced pigmentation through mTORC1

212 ligodendroglia and hypomyelination seen with Tsc1 or Tsc2 deletion in the oligodendrocyte lineage dur

213 ) is a disorder arising from mutation in the TSC1 or TSC2 gene, characterized by the development of h

214 disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of

215 TSC is caused by the loss of either the TSC1 or TSC2 genes that normally regulate the mammalian

216 esults from inactivating variants within the TSC1 or TSC2 genes, leading to constitutive activation o

217 by loss of function mutations in either the TSC1 or TSC2 genes, which regulate mTOR kinase activity.

218 Biallelic loss of TSC1 or TSC2 is a known genetic driver of angiomyolipoma

219 data suggest that loss of heterozygosity of TSC1 or TSC2 may play an important role in the developme

220 Patients are born with TSC1 or TSC2 mutations, and somatic inactivation of wild

221 is a genetic disorder caused by mutations in TSC1 or TSC2 Patients frequently have epilepsy, autism s

222 is a genetic disorder caused by mutations in TSC1 or TSC2 resulting in hyperactivity of the mammalian

223 ssociated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes.

224 TSC), caused by dominant mutations in either TSC1 or TSC2 tumour suppressor genes is characterized by

225 Inactive mutation of either TSC1 or TSC2 unleashes mTOR signaling and consequently c

226 e, mutations in the tuberous sclerosis genes TSC1 or TSC2) are due to hyperactivation of mTORC1-media

227 ons in the tuberous sclerosis complex genes (TSC1 or TSC2), resulting in hyperactive mammalian Target

228 tations in tuberous sclerosis complex genes (TSC1 or TSC2).

229 e caused by inactivating mutations in either TSC1 or TSC2, and the TSC protein complex is an essentia

230 LAM) are caused by inactivating mutations in TSC1 or TSC2, leading to mTORC1 hyperactivation.

231 berous sclerosis complex tumour suppressors, TSC1 or TSC2, or physiological activation of mTORC1 in r

232 osis Complex (TSC) is caused by mutations in TSC1 or TSC2, which encode negative regulators of the mT

233 evelopmental disorder caused by mutations in TSC1 or TSC2, which encode proteins that negatively regu

234 ivation of mTORC1, although none had loss of TSC1 or TSC2.

235 tumors and cancers with mutations in either TSC1 or TSC2.

236 n mutations in tuberous sclerosis complex 1 (TSC1) or TSC2 genes, causes protein synthesis dysregulat

237 We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type

238 sion of alphaB-crystallin was upregulated in Tsc1-/- or Tsc2-/- mouse embryonic fibroblasts, Eker rat

239 pathway is deregulated by mutations in MTOR, TSC1, PIK3CA, and PTEN in approximately 20% of ccRCCs.

240 These findings indicate that Tsc1 prevents aberrant renal growth and tumorigenesis by

241 luation of purified iNKT cells revealed that TSC1 promotes T-bet, which regulates iNKT maturation, bu

242 pG sites showed significant correlation with TSC1 protein expression.

243 TSC1 regulates TGF-beta-induced Smad2/3 phosphorylation

244 uses growth arrest, concomitant knockdown of Tsc1 restores mTORC1 activity and proximal tubular size.

245 sults demonstrate that the interplay between Tsc1-Rheb-mTORC1 signaling and Myc-dependent bioenergeti

246 ing restricts dendritic extent, with Src and Tsc1 serving as downstream mediators.

247 Suppression of hamartin expression with TSC1 shRNA viral vectors both in vitro and in vivo incre

248 In contrast, Tsc1 single-mutant mice were all alive and had far fewer

249 Furthermore, pharmacologic treatment of Tsc1 single-mutant mice with rapamycin reduced hyperphos

250 Tsc1 stabilizes Tsc2; however, the precise mechanism inv

251 rrent study, a constitutive TSC1 transgenic (Tsc1 (tg) ) mouse model was generated and characterized.

252 Tsc1 (tg) mice are more tolerant to exhaustive exercises

253 The female Tsc1 (tg) mice exhibit a higher fat to lean mass ratio a

254 Tsc1 (tg) mice have less fibrosis and inflammation in ag

255 e lifespan increased significantly in female Tsc1 (tg) mice, but not in male Tsc1 (tg) mice.

256 ly in female Tsc1 (tg) mice, but not in male Tsc1 (tg) mice.

257 n contrast, mTORC2 signaling was enhanced in Tsc1 (tg) mice.

258 indings define a novel link between Hap1 and Tsc1 that regulates neuronal mTORC1 signaling and neuron

259 1 mediates non-degradative ubiquitination of TSC1, thereby promoting TSC1-TSC2 dimerization and TSC2

260 creases its affinity for Hsp90 and displaces Tsc1, thereby providing a mechanism for equilibrium betw

261 ucible endothelial-cell-specific deletion of Tsc1 to examine mTORC1 signaling in lymphangiosarcoma.

262 In the current study, a constitutive TSC1 transgenic (Tsc1 (tg) ) mouse model was generated a

263 Elevated IL-17 production in Tsc1-/- Treg cells was reversed by in vivo knockdown of

264 n which myeloid lineage-specific deletion of Tsc1 (Tsc1(Delta/Delta)) leads to constitutive mTOR comp

265 The tuberous sclerosis 1 (TSC1)/TSC2 complex negatively regulates the activity of

266 al, whereas 21% uRCC with mutations of MTOR, TSC1, TSC2 or PTEN and hyperactive mTORC1 signalling are

267 d with expression of the upstream regulators TSC1, TSC2, AKT, p-AKT, PDPK1, PTEN, PIK3R1, or PIK3CA.

268 lex (TSC) protein complex (TSCC), comprising TSC1, TSC2, and TBC1D7, is widely recognised as a key in

269 ve ubiquitination of TSC1, thereby promoting TSC1-TSC2 dimerization and TSC2 stabilization.

270 The mammalian Tsc1-Tsc2 GTPase activating protein (GAP) heterodimer is

271 characterize the molecular requirements for TSC1-TSC2 interactions and analyze pathological point mu

272 Unexpectedly, we also found that Tsc1-Tsc2 loss activated RalA/B independently of Rheb-mT

273 ormal proliferation and induces apoptosis of TSC1-TSC2-deficient cells, both in culture and in mosaic

274 ugh the PI3K-Akt pathway, which inhibits the TSC1-TSC2-TBC1D7 complex (the TSC complex) to turn on Rh

275 ares sequence and structural similarity with Tsc1-Tsc2.

276 ves MTOR activation; however, second hits to TSC1/TSC2 are not always observed.

277 Inactivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC

278 tional kinase is an upstream effector of the TSC1/TSC2 complex that regulates mTOR signaling.

279 s hippo, Ubiquitin-proteasome system (ERK5), Tsc1/Tsc2 complex, FoxO1, wnt/beta-catenine signaling pa

280 DAPK1 mediated the disruption of the TSC1/TSC2 complex, resulting in activation of the mTOR p

281 utation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in the hyperactivation of m

282 , which develops as a result of mutations in TSC1/TSC2 genes in TSC patients, because we observed the

283 cluding Lgals3 relevant for human disease of TSC1/TSC2 inactivation and mTORC1 hyperactivity.

284 Increased mTORC1 signaling from TSC1/TSC2 inactivation is found in cancer and causes tub

285 To see whether TSC1/TSC2 loss was a common genetic event in human mesot

286 Double Tsc1/Tsc2 mutants died earlier than single mutants, and

287 s was also increased in bladder cancers with TSC1/TSC2 mutations in the TCGA database.

288 In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1

289 ntified germline and second-hit mutations in TSC1/TSC2 using next-generation sequencing.

290 ing mutations in tuberous sclerosis complex (TSC1/TSC2) genes coding for suppressors of the mechanist

291 ncy mutated genes (eg, AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2), help define some of th

292 e further delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation

293 ained activation of the MEK-ERK pathway in a TSC1/TSC2/TBC1D7 protein complex and mTORC1-independent

294 dney-specific inactivation of either Pkd1 or Tsc1 using an identical Cre (KspCre) results in aggressi

295 e mTORC1 in mouse tissue, we deleted hepatic Tsc1 using Cre adenovirus.

296 Here we report that specific ablation of Tsc1 using the mesenchymal stem cell-osteoblast lineage

297 Mutations of RAS, PTEN, and TSC1, which cause mTORC1 hyperactivation, enhance immuno

298 f the Tuberous Sclerosis Complex (TSC) gene, Tsc1, which inhibits the mammalian target of rapamycin (

299 n general, TSC2 disease was more severe than TSC1, with more subependymal giant cell astrocytomas and

300 Cell-specific loss of Tsc1 within nestin-expressing cells in adult mice leads