ライフサイエンスコーパス: menin

1 pendent and independent of the MLL cofactor, Menin.

2 , which interacts with the tumor suppressor, menin.

3 and mimics the key interactions of MLL with menin.

4 hly conserved between Nematostella and human menin.

5 ment of MLL that are required for binding to menin.

6 about the normal hematopoietic functions of menin.

7 tation of the MEN1 gene that encodes protein menin.

8 des the nuclear protein and tumor suppressor menin.

9 MEN1 gene, which encodes a tumor suppressor, menin.

10 or suppressor gene Men1 that encodes protein menin.

11 n1, encodes a protein 50% identical to human menin.

12 patients, Men1, encodes a tumor suppressor, menin.

13 he gene for which encodes a nuclear protein, menin.

14 ion crystal structures of the complexes with menin.

15 d in short interactions with the backbone of menin.

16 mia 1, and mixed lineage leukemia 1 cofactor menin.

17 erative RAF/MAPK pathway by tumor suppressor menin.

18 helium-derived growth factor (LEDGF/p75) and MENIN.

19 ins, which also involve the tumor suppressor menin.

20 monstrate post-translational modification of menin.

21 osely mimic all key interactions of MLL with menin.

22 r (LEDGF/p75; encoded by the PSIP1 gene) and MENIN.

23 ts from mutations in the MEN1 gene, encoding menin.

24 nactivating mutations in MEN1, which encodes menin, a component of a histone methyltransferase comple

25 beta2 expression is intact in MEFs devoid of menin, a component of MLL1 and MLL2 H3K4MT complexes.

26 or the methylation of a subset of Hox genes, menin, a component of the Mll1 and Mll2 complexes, is re

27 Menin, a product of the MEN1 tumor suppressor gene, is a

28 form a macromolecular complex that includes menin, a product of the MEN1 tumor suppressor gene, whic

29 he MLL histone methyl transferase complex by menin, a protein important for MLL-associated leukemic t

30 Here we show that menin, a protein previously characterized as an endocrin

31 ere that SKIP also associates with c-Myc and Menin, a subunit of the MLL1 histone methyltransferase (

32 Here, we show that menin ablation enhances Hedgehog signaling, a proprolife

33 These results suggest that menin activates the transcription of differentiation-reg

34 Menin activates transcription by means of a mechanism in

35 Although menin acts as an oncogenic cofactor for mixed lineage le

36 Menin also interacts with mixed lineage leukaemia protei

37 Importantly, menin also serves as a critical oncogenic cofactor of ML

38 led excision of the Men1 gene, which encodes menin, ameliorated preexisting hyperglycemia in streptoz

39 st the presence of cell-specific factors for menin and a permissive endocrine environment for MEN1 tu

40 ndings demonstrate a functional link between menin and ASK in the regulation of cell proliferation.

41 INK4c) correlates with reduced expression of menin and E2F1 but is unaffected by acute cell-cycle arr

42 s 5 and 44 are required for interaction with menin and for the transformation of hematopoietic progen

43 These findings uncover a novel link between menin and Hedgehog signaling whereby menin/PRMT5 epigene

44 o IBD directly and inhibits both the IBD-MLL/menin and IBD-IN interactions.

45 d-lineage leukemia (MLL) fusion proteins and menin and is required for leukemic transformation.

46 rimary hippocampal cultures demonstrate that menin and its calpain-dependent C-terminal fragment (C-m

47 on between the tumour-suppressor function of menin and its suppression of JUND-activated transcriptio

48 t was accompanied by reduced islet levels of menin and its targets.

49 Several studies have shown that both MENIN and LEDGF/p75 are required for efficient MLL-fusio

50 that the compound binds to the MLL pocket in menin and mimics the key interactions of MLL with menin.

51 Menin and miR-24 expression levels were measured in the

52 he protein-protein interaction (PPI) between menin and mixed lineage leukemia (MLL) plays a critical

53 aled that the c-Myb/GATA-3 complex contained Menin and mixed lineage leukemia (MLL).

54 Although menin and MLL fusion proteins cooperate to activate Home

55 lock the protein-protein interaction between menin and MLL fusion proteins that plays an important ro

56 scription by cooperative interaction between menin and MLL plays a central role in menin's activity a

57 bivalent protein-protein interaction between menin and MLL.

58 rate the lack of genetic interaction between menin and MLL1 in steady-state or regenerative hematopoi

59 t rather than working together as a complex, menin and MLL1 regulate distinct pathways during normal

60 n LEDGF at a distinct surface formed by both menin and MLL1.

61 Mutant islets showed increased Menin and nuclear p27.

62 The interaction between menin and oncogenic mixed lineage leukemia (MLL) fusion

63 proteins interact with the tumor suppressor menin and with the Hoxa9 locus in vivo.

64 ar transcription start sites, interacts with menin, and inhibits MLL complex assembly, resulting in d

65 c-Myb, GATA-3, Menin, and mixed lineage leukemia (MLL) bound to CGRE in

66 matostella menin is a close homolog of human menin, and these two proteins likely have very similar s

67 indicating that the synaptogenic actions of menin are specific to cholinergic regulation.

68 ructural basis for understanding the role of menin as a tumor suppressor protein and as an oncogenic

69 Together, our results suggest menin as an important novel negative regulator of AKT ki

70 identified a compound targeting the protein menin as an inhibitor of tumor cell growth in vitro and

71 We identify the COOH terminus of menin as the domain that mediates the specific interacti

72 This menin-associated complex methylates histone H3 on lysine

73 subtle mutations in menin NLSs do not affect menin association with chromatin, they abolish menin bin

74 ly 10 nM) through two motifs, MBM1 and MBM2 (menin binding motifs 1 and 2).

75 nin association with chromatin, they abolish menin binding to the IGFBP-2 promoter in vivo.

76 first time, a novel biochemical activity of menin, binding to DNA, and link its DNA binding to the r

77 gth SON for chromatin occupancy but lack the menin-binding ability, thereby antagonizing full-length

78 Here we show that menin binds the 5'-untranslated region (5'-UTR) of the C

79 Menin binds the JUN family transcription factor JUND and

80 ich are considered functionally unrelated to menin but are sensitive markers of cell state.

81 ms of MLL retain an ability to interact with menin but not other identified complex components.

82 HIV-1 Tat transactivation requires c-Myc and Menin, but not MLL1 or H3K4me3.

83 mice, transgenic mice overexpressing a human menin cDNA in osteoblasts driven by the 2.3-kb Col1a1 pr

84 Notably, wild-type menin completely represses ASK-induced cell proliferatio

85 MLL recruitment into the c-Myb-GATA-3-Menin complex was associated with the formation Th2 memo

86 nly a partial structure of the LEDGF/p75-MLL-MENIN complex.

87 These structures show that menin contains a deep pocket that binds short peptides o

88 brate Lymnaea stagnalis, we demonstrate that menin coordinates subunit-specific transcriptional regul

89 nown about the molecular mechanisms by which menin decreases the oncogenic effects on cell morphology

90 ne expression was only modestly decreased in menin-deficient HSCs.

91 The predicted menin Delta(184-218) mutant has an in-frame deletion of

92 The transfected menin Delta(184-218) mutant was well expressed and fully

93 topoietic stem cells (HSC) in the absence of menin, despite normal initial homing of progenitors to t

94 eta-cells that lack the MEN1-encoded protein menin develop into tumors.

95 Menin directly activates Hoxa9 expression, at least in p

96 Menin directly binds the 5'-UTR in a sequence-independen

97 Here we show that menin directly binds to double-stranded DNA.

98 Menin directly interacts with protein arginine methyltra

99 Here, we show that menin directly regulates expression of the cyclin-depend

100 Depletion of menin does not affect the expression of Drosha and CBP80

101 Menin downregulates the level of active AKT and its kina

102 Consistent with signaling downstream of menin, ectopic expression of both Hoxa9 and Meis1 rescue

103 ation factor HLXB9 as a downstream target of menin (encoded by MEN1).

104 Together, our results indicate that menin enhances the caspase 8 expression by binding the c

105 ls but had little impact on let-7a levels in menin-excised cells.

106 rs2 knockdown decreased let-7a processing in menin-expressing cells but had little impact on let-7a l

107 miR-24 was shown to negatively regulate menin expression by luciferase assay.

108 cancer and benign prostate tissue, and high menin expression correlates with poor overall survival o

109 t MEN1 gene replacement therapy can generate menin expression in pituitary tumors, and significantly

110 Menin expression is higher in CRPC than in both hormone-

111 Abrogation of menin expression phenocopies loss of MLL and reveals a c

112 er cancers, insofar as we found that loss of menin expression was also associated with AKT activation

113 Menin expression was decreased in advanced CCA specimens

114 Menin expression was higher in the Men1.rAd5-treated mic

115 We recently reported that c-Myb, GATA-3, and Menin form a core transcription complex that regulates G

116 Therefore, c-Myb, GATA-3, and Menin form a core transcription complex that regulates G

117 This pathway disrupts nuclear menin function, leading to hypergastrinemia and associat

118 Menin functions as a component of a histone methyltransf

119 Menin functions as a critical oncogenic cofactor of mixe

120 Thus, menin functions in vivo during osteogenesis and is requi

121 of patients with MEN1 have mutations in the menin gene.

122 Menin has been shown to interact with SET-1 domain-conta

123 re, we report the first crystal structure of menin homolog from Nematostella vectensis.

124 mary-let-7a (pri-let-7a) are not affected by menin; however, the levels of mature let-7a are substant

125 MLL interacts with menin in a bivalent mode involving 2 N-terminal fragment

126 cular therapy, and suggest central roles for menin in altered epigenetic functions underlying the pat

127 surements, we established that MBM1 binds to menin in an extended conformation.

128 To examine the in vivo function of menin in bone, we conditionally inactivated Men1 in matu

129 These studies uncover an important role for menin in both normal hematopoiesis and myeloid transform

130 t high-resolution crystal structure of human menin in complex with a small-molecule inhibitor of the

131 n1 (Men1(f/f)) mice to generate mice lacking menin in differentiating osteoblasts (OC-Cre;Men1(f/f) m

132 ce, we have investigated the requirement for menin in hematopoiesis and myeloid transformation.

133 ations reveal a novel and essential role for menin in HSC homeostasis that was most apparent during s

134 e we present the crystal structures of human menin in its free form and in complexes with MLL1 or wit

135 Transgenic expression of menin in maternal beta-cells prevented islet expansion a

136 Tissue-specific inactivation of menin in Pax3- or Wnt1-expressing neural crest cells lea

137 Deletion of menin in Pax3-expressing somite precursors also produces

138 Here we showed that ectopic expression of menin in pretumor beta-cells increases islet cell adhesi

139 Consistent with an essential role for menin in regulating beta-cell adhesion in vivo, accumula

140 To extend the role of menin in repressing cell cycle in cultured cells to in v

141 loss of MLL and reveals a critical role for menin in the maintenance of Hox gene expression.

142 t the 5'-UTR of the caspase 8 locus bound by menin in vivo.

143 epithelium-derived growth factor (LEDGF) by menin indicates that menin is a molecular adaptor coordi

144 enhanced proliferation when combined with a menin inhibitor.

145 We determined menin-inhibitor co-crystal structures and found that the

146 ndings define SON as a fine-tuner of the MLL-menin interaction and reveal short SON overexpression as

147 Blocking the MLL-menin interaction by the expression of a dominant negati

148 work establishes the molecular basis of the menin interaction with MLL and MLL fusion proteins and p

149 nt of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a

150 characterize the molecular basis of the MLL-menin interaction.

151 Although menin interacts with a variety of nuclear proteins inclu

152 Moreover, menin interacts with activator of S-phase kinase (ASK),

153 Here, we report that menin interacts with AKT1 in vitro and in vivo.

154 Here, we show that menin interacts with arsenite-resistant protein 2 (ARS2)

155 Despite its importance, how menin interacts with many distinct partners and regulate

156 Menin interacts with many proteins and is involved in a

157 Menin interacts with several transcription factors, incl

158 es its endocrine role, the Men1 gene product menin interacts with the mixed lineage leukemia (MLL) pr

159 Our further studies revealed that menin interacts with the scaffold protein, IQ motif cont

160 ing gene transcription than merely targeting menin into the nucleus.

161 Together, these results define a novel menin-IQGAP1 pathway that controls cell migration and ce

162 y high sequence similarity, the Nematostella menin is a close homolog of human menin, and these two p

163 rowth factor (LEDGF) by menin indicates that menin is a molecular adaptor coordinating the functions

164 Although menin is a nuclear protein and directly binds to DNA thr

165 Menin is a nuclear protein encoded by a tumor suppressor

166 Menin is a tumor suppressor protein that is encoded by t

167 Menin is a tumor suppressor required to prevent multiple

168 Menin is a tumor suppressor that is mutated in patients

169 Though menin is a tumor suppressor, its molecular mechanism of

170 Menin is a tumour suppressor protein whose loss or inact

171 n1, in diabetic conditions, and suggest that menin is a vital regulator in pathogenesis of diabetes.

172 Menin is an essential oncogenic cofactor for mixed linea

173 We now show that menin is associated with a histone methyltransferase com

174 In addition, menin is associated with RNA polymerase II whose large s

175 immunoprecipitation experiments reveal that menin is bound to the Hoxc8 locus.

176 Menin is encoded by the tumor suppressor gene MEN1 that

177 Furthermore, menin is essential for maintenance of MLL-associated but

178 However, it is unclear whether menin is essential for repression of cell proliferation,

179 Although menin is known to be involved in regulating cell prolife

180 Whereas menin is largely regarded as a nuclear protein, our data

181 nce of these 2 proteins and demonstrate that menin is not a requisite cofactor for MLL1 during normal

182 Menin is predominantly an alpha-helical protein with the

183 Menin is the product of the tumor suppressor gene Men1 t

184 r data support the idea that one function of menin is to modulate Jun activity in a manner dependent

185 r suppressor gene, which encodes the protein menin, is known to induce synapse formation and plastici

186 Whereas the protein product of MEN1, menin, is ubiquitously expressed, somatic loss of the re

187 transcription factors, it is unknown whether menin itself can directly bind DNA.

188 The menin-JUND interaction blocks JUN N-terminal kinase (JNK

189 Several MEN1 missense mutations disrupt the menin-JUND interaction, suggesting a correlation between

190 ve GSK-3beta are elevated in beta cells with menin knockdown, in MEN1-associated beta cell tumors (in

191 Overexpression of menin leads to inhibition of Ras-transformed cells.

192 onal regulator of pregnancy, repressed islet menin levels and stimulated beta-cell proliferation.

193 Menin loss modestly impaired blood neutrophil, lymphocyt

194 c-Met in insulinomas of two mouse models of menin loss.

195 nthetic lethal interaction in the setting of menin loss.

196 Together, these results suggest that menin may act as a scaffold protein in coordinating acti

197 miR-24-dependent expression of menin may be important in the regulation of nonmalignant

198 p-regulates caspase 8 expression and whether menin-mediated caspase 8 expression plays a role in repr

199 ermore, each of the NLSs is also crucial for menin-mediated induction of caspase 8 expression.

200 The COOH terminus of menin mediates binding to DNA, but MEN1 disease-derived

201 leukemia (MLL1) gene acts independently from menin (Men1) in the hematopoietic system.

202 Menin (MEN1) is a tumor-suppressor protein in neuroendoc

203 Based on the menin-MI-2 structure, we developed MI-2-2, a compound th

204 sponding to MBM1 efficiently dissociates the menin-MLL complex.

205 ble of efficiently sequestering IBD from the menin-MLL complex.

206 Analysis of the menin-MLL inhibitor complexes revealed that the backbone

207 ckbone carbonyls may improve the activity of menin-MLL inhibitors as much as 5- to 10-fold.

208 erent sites in the thienopyrimidine class of menin-MLL inhibitors considerably improved their inhibit

209 and structure-property relationships for the menin-MLL inhibitors, demonstrates challenges in optimiz

210 for development of inhibitors targeting the menin-MLL interaction as a novel therapeutic strategy in

211 Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits t

212 of inhibitors for effective targeting of the menin-MLL interaction in leukemia and demonstrate a proo

213 nstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment

214 nds, resulting in MIV-6R, which inhibits the menin-MLL interaction with IC50 = 56 nM.

215 mplex with a small-molecule inhibitor of the menin-MLL interaction, MI-2.

216 ioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their

217 el class of small-molecule inhibitors of the menin-MLL interaction, the hydroxy- and aminomethylpiper

218 ectly interacts with the MLL complex via the menin-MLL subunit.

219 potent and cell-permeable inhibitors of the menin-MLL1 interaction.

220 macrocyclic peptidomimetic inhibitors of the menin-MLL1 interaction.

221 Targeting the menin-MLL1 protein-protein interaction represents a prom

222 hermore, our data support the development of menin-MLL1-disrupting drugs as safe and selective leukem

223 produced protein null alleles of Drosophila menin (mnn1) and have over expressed the Mnn1 protein.

224 In vitro, menin modulates osteoblastogenesis and osteoblast differ

225 In conclusion, the menin mutant exhibits selective loss of the TGF-beta sig

226 Importantly, these MEN1 disease-related menin mutants also fail to repress cell proliferation as

227 Notably, MEN1 disease-related menin mutants have reduced binding to PRMT5, and fail to

228 A subset of tumor-derived menin mutants lacks the associated histone methyltransfe

229 Interestingly, disease-related COOH-terminal menin mutants that do not interact with ASK completely f

230 Although subtle mutations in menin NLSs do not affect menin association with chromati

231 ll proliferation, whereas complementation of menin-null cells with menin reduces cell proliferation.

232 Furthermore, complementation of menin-null cells with wild-type menin represses S-phase

233 MEIS1 gene expression, and decreased MLL and menin occupancy in the HOXA9 gene locus.

234 The MEN1 gene encodes the tumor suppressor menin of 610 amino acids that has multiple protein partn

235 r, our results suggest that the influence of menin on synapse formation and synaptic plasticity occur

236 Immunoprecipitation with menin or ubiquitin was used to demonstrate post-translat

237 In B cells, menin- or MLL1-regulated genes can be classified into 3

238 Menin overexpression decreased proliferation, angiogenes

239 Therefore, osteoblast menin plays a key role in bone development, remodeling,

240 Here, we show that menin plays a previously unappreciated and critical role

241 Notably, the MEN1-derived menin point mutants lose their ability to bind the caspa

242 ther tumors caused by mutations in the GNAS, menin, PRKAR1A, AIP, and p27 (CDKN1B) genes, respectivel

243 between menin and Hedgehog signaling whereby menin/PRMT5 epigenetically suppresses Hedgehog signaling

244 aberrant Hox gene expression mediated by MLL-menin promoter-associated complexes, and specifically ab

245 In contrast, menin promotes gene transcription by binding the transcr

246 ations in the MEN1 gene that encodes for the menin protein are the predominant cause for hereditary M

247 Inhibition of miR-24 increased menin protein expression while decreasing proliferation,

248 Mammalian menin protein is associated with chromatin modifying com

249 miR-24 miRNA and menin protein levels were manipulated in vitro in Mz-ChA

250 om mutations in the MEN1 gene, which encodes menin protein.

251 teins is dependent on their interaction with menin, providing basis for therapeutic intervention.

252 MLL tethers Menin, RbBP5, and ASH2L to its occupied sites during mit

253 Menin recruits PRMT5 to the promoter of the Gas1 gene, a

254 eas complementation of menin-null cells with menin reduces cell proliferation.

255 its calpain-dependent C-terminal fragment (C-menin) regulate the subunit-specific transcription and s

256 1, and much larger groups of (2) exclusively menin-regulated and (3) exclusively MLL1-regulated genes

257 Confocal microscopy analysis revealed that menin regulates AKT1 in part by reducing the translocati

258 proliferation in vitro, it is not clear how menin regulates cell cycle and whether mutation of Men1

259 erefore, we tested the novel hypothesis that menin regulates cholangiocarcinoma proliferation.

260 We investigated how menin regulates expression of the gastrin gene and induc

261 s of hematopoietic recovery, suggesting that menin regulates molecular pathways that are essential du

262 mentation of menin-null cells with wild-type menin represses S-phase entry.

263 ethylation and binding with tumor suppressor menin, respectively.

264 Loss of function of either MLL or menin results in down-regulation of p27Kip1 and p18Ink4c

265 Acute genetic ablation of menin reverses aberrant Hox gene expression mediated by

266 Based on our analysis, we propose that menin's ability to maintain cellular and microenvironmen

267 etween menin and MLL plays a central role in menin's activity as a tumor suppressor.

268 n and provide a mechanistic understanding of menin's function in these processes that may be used for

269 an analogous cholinergic mechanism underlies menin's synaptogenic function in the vertebrate CNS.

270 s for people with diabetes and for targeting menin-sensitive endocrine tumors.

271 Menin shows bidirectional effects acting positively on c

272 A very interesting feature of menin structure is the presence of a large central cavit

273 Through interaction with AKT1, menin suppresses both AKT1-induced proliferation and ant

274 llectively unravel a novel mechanism whereby menin suppresses cell proliferation, at least partly by

275 ine 4 methylation, the precise basis for how menin suppresses gene expression and proliferation of pa

276 However, the precise mechanism by which menin suppresses gene expression is not well understood.

277 esults suggest a molecular mechanism whereby menin suppresses MEN1 tumorigenesis at least partly thro

278 inding the caspase 8 locus, and suggest that menin suppresses MEN1 tumorigenesis, at least in part, b

279 chemical function, little is known as to how menin suppresses tumorigenesis.

280 e were significantly increased in the Col1a1-Menin-Tg mice.

281 is no obvious conserved structural domain in menin that suggests a biochemical function, little is kn

282 In the absence of menin, the endocrine pancreas showed increase in cell pr

283 We have recently shown that menin, the MEN1 protein product, interacts with mixed li

284 This gene encodes the protein menin, the overexpression of which inhibits cell prolife

285 d calpain-dependent proteolytic fragments of menin, the product of the MEN1 tumor suppressor gene, in

286 Menin, the product of the multiple endocrine neoplasia t

287 s retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved

288 in the COOH terminus abolish the ability of menin to bind DNA.

289 Thus, SKIP acts with c-Myc and Menin to promote HIV-1 Tat:P-TEFb transcription at an el

290 translocation, but compromise the ability of menin to repress expression of the endogenous insulin-li

291 ne carrier had, in addition to the wild-type menin transcript, an aberrant transcript resulting from

292 However, it remains unclear how menin up-regulates caspase 8 expression and whether meni

293 We previously reported that menin up-regulates the caspase 8 expression and promotes

294 Gastrin-induced nuclear export of menin via cholecystokinin B receptor (CCKBR)-mediated ac

295 Once exported from the nucleus, menin was ubiquitinated and degraded by the proteasome.

296 Menin, which directly binds MLL, has been identified as

297 ocyclic peptidomimetic (MCP-1), 34, binds to menin with a K(i) value of 4.7 nM and is >600 times more

298 erestingly, we found that MLL interacts with menin with a nanomolar affinity (K(d) approximately 10 n

299 e developed MI-2-2, a compound that binds to menin with low nanomolar affinity (K(d) = 22nM) and very

300 Direct association of menin with MLL fusion proteins is required for MLL fusio