ライフサイエンスコーパス: menin

1 osely mimic all key interactions of MLL with menin.

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

3 pendent and independent of the MLL cofactor, Menin.

4 , which interacts with the tumor suppressor, menin.

5 and mimics the key interactions of MLL with menin.

6 hly conserved between Nematostella and human menin.

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

8 about the normal hematopoietic functions of menin.

9 tation of the MEN1 gene that encodes protein menin.

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

11 or suppressor gene Men1 that encodes protein menin.

12 monstrate post-translational modification of menin.

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

14 des the nuclear protein and tumor suppressor menin.

15 ion crystal structures of the complexes with menin.

16 d in short interactions with the backbone of menin.

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

18 slational repression by miRNA (microRNA)-673/menin.

19 erative RAF/MAPK pathway by tumor suppressor menin.

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

21 ins, which also involve the tumor suppressor menin.

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

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

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

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

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

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

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

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

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

31 Menin activates transcription by means of a mechanism in

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

33 Menin also interacts with mixed lineage leukaemia protei

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

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

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

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

38 d significantly better responses to combined menin and FLT3 inhibition than to single-drug or vehicle

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

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

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

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

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

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

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

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

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

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

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

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

51 The protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) plays a critic

52 Although menin and MLL fusion proteins cooperate to activate Home

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

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

55 bivalent protein-protein interaction between menin and MLL.

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

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

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

59 Mutant islets showed increased Menin and nuclear p27.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

75 Menin binds the JUN family transcription factor JUND and

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

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

78 l molecule (VTP-50469) that targets the MLL1-Menin chromatin complex.

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

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

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

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

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

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

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

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

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

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

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

90 Menin directly activates Hoxa9 expression, at least in p

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

92 Menin directly interacts with protein arginine methyltra

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

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

95 Menin downregulates the level of active AKT and its kina

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

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

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

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

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

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

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

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

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

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

106 Menin expression was decreased in advanced CCA specimens

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

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

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

110 VTP50469 displaced Menin from protein complexes and inhibited chromatin occ

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

112 Menin functions as a component of a histone methyltransf

113 Menin functions as a critical oncogenic cofactor of mixe

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

137 M-808 represents a promising, covalent menin inhibitor for further optimization and evaluation

138 as a highly potent and efficacious covalent menin inhibitor.

139 enhanced proliferation when combined with a menin inhibitor.

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

141 the menin-MLL interaction (hereafter called menin inhibitors).

142 e resulted in the discovery of highly potent menin inhibitors, as exemplified by compound 42 (M-89).

143 re-based optimization of a class of covalent menin inhibitors, which led to the discovery of M-808 (1

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

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

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

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

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

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

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

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

152 Menin interacts with many proteins and is involved in a

153 Menin interacts with several transcription factors, incl

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

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

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

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

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

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

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

161 Menin is a nuclear protein encoded by a tumor suppressor

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

163 Menin is a tumor suppressor required to prevent multiple

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

165 Menin is a tumour suppressor protein whose loss or inact

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

167 Menin is an essential oncogenic cofactor for mixed linea

168 Menin is encoded by the tumor suppressor gene MEN1 that

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

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

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

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

173 Menin is predominantly an alpha-helical protein with the

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

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

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

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

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

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

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

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

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

183 Menin loss modestly impaired blood neutrophil, lymphocyt

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

185 nthetic lethal interaction in the setting of menin loss.

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

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

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

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

190 Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a pote

191 The interaction of menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and p

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

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

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

195 Inhibition of the menin-mixed lineage leukemia (MLL) protein-protein inter

196 Our data suggest that combined menin-MLL and FLT3 inhibition represents a novel and pro

197 ling after pharmacological inhibition of the menin-MLL complex revealed specific changes in gene expr

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

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

200 Combining menin-MLL inhibition with specific small-molecule kinase

201 A new orally bioavailable Menin-MLL inhibitor (VTP-50469) appears to promote their

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

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

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

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

206 promising preclinical studies with XPO1 and menin-MLL inhibitors.

207 ew class of small-molecule inhibitors of the menin-MLL interaction (hereafter called menin inhibitors

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

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

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

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

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

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

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

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

216 Targeting the menin-MLL protein-protein interaction is a new therapeut

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

218 e to our knowledge, profound activity of the menin-MLL1 inhibitor as a single agent in clinically rel

219 As a step toward clinical translation of menin-MLL1 inhibitors, we report development of MI-3454,

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

221 macrocyclic peptidomimetic inhibitors of the menin-MLL1 interaction.

222 ent and orally bioavailable inhibitor of the menin-MLL1 interaction.

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

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

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

226 In vitro, menin modulates osteoblastogenesis and osteoblast differ

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

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

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

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

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

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

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

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

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

236 Menin overexpression decreased proliferation, angiogenes

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

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

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

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

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

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

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

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

245 e of 1.4 nM and effectively engages cellular menin protein at low nanomolar concentrations.

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

247 Mammalian menin protein is associated with chromatin modifying com

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

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

250 o-crystal structure of M-808 in complex with menin provides a structural basis for their high-affinit

251 -crystal structure of M-89 in a complex with menin provides the structural basis for their high-affin

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

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

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

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

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

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

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

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

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

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

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

296 M-89 binds to menin with a K(d) value of 1.4 nM and effectively engage

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