ライフサイエンスコーパス: MCL1

1 MCL1 (ML1 myeloid cell leukemia 1), a Bcl-2 (B- cell lym

2 MCL1 has effects similar to those of BCL2, up-regulation

3 MCL1 is a member of the BCL2 family that is highly regul

4 MCL1 is a viability-promoting member of the BCL2 family

5 MCL1 is essential for the survival of stem and progenito

6 MCL1 pathway alterations were found in 22% of cases and

7 MCL1 thus sets the stage for the development of lymphoma

8 MCL1 was defined as a target for downregulation by miR-3

9 MCL1, which encodes the antiapoptotic protein MCL1, is a

10 g pattern of myeloid cell leukemia factor 1 (MCL1) pre-mRNA.

11 ro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the developm

12 Here, antiapoptotic myeloid cell leukemia 1 (MCL1) was found to prolong survival upon T cell stimulat

13 cally, synthesis of myeloid cell leukemia 1 (MCL1), an antiapoptotic protein known to play a role in

14 phosphorylation of myeloid cell leukemia 1 (MCL1), another viability-promoting BCL2 family member.

15 tinguishes myeloid cell leukemia sequence 1 (MCL1) from BCL2 dependence in myeloma cell lines.

16 ription of myeloid cell leukemia sequence-1 (MCL1), an antiapoptotic B cell leukemia-2 family member.

17 , BCL2, BCL-XL, and myeloid cell leukemia 1 [MCL1]) remain poorly understood.

18 7 [19%]), MYC (23 [12%]), ARID1A (21 [11%]), MCL1 (19 [10%]), PIK3CA (17 [9%]), ERBB2 (16 [8%]), PTEN

19 tional repressors that preferentially affect MCL1 due to its short mRNA half-life.

20 n the G2/M phase and was not found to affect MCL1 turnover.

21 ction and cell death induction via alternate MCL1 splicing.

22 H3 and H4 of the H3K4 methylated alternative MCL1 exon 2 nucleosome.

23 Mice expressing an MCL1 transgene in hematolymphoid tissues have now been m

24 pendent phosphorylation, which results in an MCL1 band shift and is induced by events in G(2)/M or pr

25 eport shows that transgenic expression of an MCL1 protein enhances survival of memory CD8(+) T cells

26 (BCL2L2), BCLb (BCL2L10), BFL1 (BCL2A1) and MCL1 -- also cooperate with MYC to accelerate leukemogen

27 These included the BCL2L1 and MCL1 combination, which was also effective in imatinib-r

28 ggest that combination of TKIs with BCL6 and MCL1 inhibitors may potentially lead to the complete era

29 findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, mess

30 EGR2, which in turn leads to cell growth and MCL1-mediated cell survival.

31 d a close relationship between FBW7 loss and MCL1 overexpression.

32 Transcriptional repressors and MCL1 shRNAs induced apoptosis in the same cancer cell li

33 examined the expression of BCL2, BCL-XL, and MCL1 in primary human hematopoietic subsets and leukemic

34 optotic factors, including BCL2, BCL-XL, and MCL1.

35 ersus stabilized expression of antiapoptotic MCL1 is thus controlled by N-terminal truncation as well

36 imals revealed lower levels of antiapoptotic MCL1, a higher propensity to apoptosis, and a diminished

37 During mitotic arrest, MCL1 protein levels decline markedly, through a post-tra

38 nificant enrichment in cancer genes (such as MCL1, BCL2, ETS1, or JUN) that directly or indirectly af

39 nd translation of key survival genes such as MCL1.

40 f transcripts with a short half-life such as MCL1.

41 correlated with higher BCL2:BCL2L1 and BCL2:MCL1 mRNA expression ratios.

42 Because MCL1 is a major mechanism of resistance to ABT-737, thes

43 Low MCL1 expression and high BIM:MCL1 or BIM:BCL2 ratios in leukemic cells correlated wit

44 A mutant of MCL1 that lacks PCNA binding (MCL1(Delta)(4A)) could not inhibit cell cycle progressio

45 USP9X binds MCL1 and removes the Lys 48-linked polyubiquitin chains

46 BCL2-like structural folds belonging to both MCL1 and BAK.

47 ctions to displace BAK from sequestration by MCL1 and BCL-X(L).

48 In contrast, MCL1(Delta)(4A) retained its anti-apoptotic function in

49 tion correlated with the level of cyclin D1, MCL1, and phospho-BAD, which also correlated with FGFR-i

50 ved oncoproteins including c-MYC, Cyclin D1, MCL1, and the PIM1/2 kinases themselves.

51 ds, including anthracyclines, that decreased MCL1 expression.

52 ws turnover of the normally rapidly degraded MCL1 protein; however, okadaic acid and taxol induce ERK

53 modifications may contribute to dysregulated MCL1 expression in cancer and represent targets for prom

54 e rescued by physiological levels of ectopic MCL1 expression.

55 enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these p

56 ases MCL1 polyubiquitination, which enhances MCL1 turnover and cell killing by the BH3 mimetic ABT-73

57 multiple myeloma survival genes, especially MCL1, TNK2, CDK11, and WBSCR22, exhibited differential e

58 estores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mecha

59 proteins that are constitutively expressed, MCL1 is inducibly expressed in cells that are recently e

60 Overall, expression MCL1 can increase during the induction of cell death as

61 icting navitoclax sensitivity, and extensive MCL1*BAK complexes predicting A1210477 sensitivity.

62 In fact, MCL1, not other Bcl-2 family proteins, contained the PCN

63 ed to a decrease in the antiapoptotic factor MCL1, which is often upregulated in NSCLC.

64 The RR by histology was as follows: MCL1, 38%; MCL2, 37%; IMC, 28%; and SLL, 14%.

65 1 released the proapoptotic protein BAK from MCL1, and Bak deficiency conferred resistance to transcr

66 growth and expression of the MYC target gene MCL1.

67 educed expression of the antiapoptotic genes MCL1 and BCLXL.

68 essing expression of the antiapoptotic genes MCL1, XIAP, BCL-xL, SURVIVIN, and MDM2.

69 reased transcription of antiapoptotic genes (MCL1 and BFL1).

70 Interestingly, high MCL1 to BCL-xl messenger RNA determines whether the cell

71 of mouse and human results that explain how MCL1 can block an important negative consequence of MYC

72 cell stimulation, and mice expressing human MCL1 as a transgene exhibited a skewing in the proportio

73 A 162-base pair segment of the human MCL1 5'-flank was found to direct luciferase reporter ac

74 nhibitor PD 98059) prevented the increase in MCL1 expression and caused rapid cell death by apoptosis

75 family was found to precede the increase in MCL1 expression produced by 12-O-tetradecanoylphorbol 13

76 the mechanism of the TPA-induced increase in MCL1 expression seen in myelomonocytic cells at early st

77 To assess whether this increase in MCL1 expression was associated with enhanced protection

78 The DNA damage-induced increase in MCL1 mRNA did not depend upon p53 as it was seen in cell

79 The increase in MCL1 occurred rapidly and was transient, levels of the M

80 activation was necessary for the increase in MCL1, as inhibition of the increase in ERK phosphorylati

81 gen-specific CD8(+) T cells were observed in MCL1 transgenic mice.

82 phosphorylation associated with reduction in MCL1 levels and phosphorylation, illustrating a potent m

83 hibitors is maintained; however, a switch in MCL1 dependence occurs.

84 al EBV super-enhancer (ESE) targets included MCL1, IRF4, and EBF.

85 athways and differently-expressed, including MCL1/miR-20a-5p, APOL3/miR-4763-5p, PLD1/miR-4717-3p, an

86 resses other anti-apoptotic genes, including MCL1 and BCL2A1.

87 not have this marked effect did not increase MCL1.

88 polysaccharide, okadaic acid) also increased MCL1 expression.

89 d USP9X expression correlates with increased MCL1 protein in human follicular lymphomas and diffuse l

90 Knockdown of USP9X increases MCL1 polyubiquitination, which enhances MCL1 turnover an

91 kadaic acid and taxol induce ERK-independent MCL1 phosphorylation at additional discrete sites.

92 nt (BAX) and others through p53-independent (MCL1) pathways.

93 bule-damaging agents, such as taxol, induced MCL1 phosphorylation associated with a band shift to dec

94 kinase (ERK) activation blocked TPA-induced MCL1 phosphorylation but not the taxol-induced band shif

95 TPA-induced MCL1 phosphorylation occurred rapidly and was not associ

96 and NOXA, which can then bind to and inhibit MCL1.

97 hway through which many BH3 mimetics inhibit MCL1 and suggest the potential use of these agents as ad

98 siRNA-fortilin) did not affect intracellular MCL1 level, the depletion of intracellular MCL1 by siRNA

99 r MCL1 level, the depletion of intracellular MCL1 by siRNA-MCL1 was associated with the significant r

100 udies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma,

101 both N-terminally truncated and full-length MCL1 contain sequences enriched in proline, glutamic aci

102 Fortilin, like MCL1, was rapidly inducible in serum-stimulated human ao

103 Low MCL1 expression and high BIM:MCL1 or BIM:BCL2 ratios in

104 nked polyubiquitin chains that normally mark MCL1 for proteasomal degradation.

105 compared with ML-1 cells expressing maximal MCL1 on exposure to phorbol-12-myristate-13- acetate.

106 We identified the Bcl2 family member MCL1 and several 26S proteasome subunits among the most

107 The antiapoptotic BCL2 family member MCL1 is normally up- and down-modulated in response to e

108 sion of the pro-survival BCL-2 family member MCL1, which occurs via inhibition of STAT5A.

109 on expression of another BCL2 family member, MCL1, a gene expressed during ML-1 cell differentiation.

110 Another antiapoptotic family member, MCL1, exhibits a difference in electrophoretic mobility

111 -regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic dr

112 s exhibit enhanced survival and express more MCL1 and less Bim.

113 Moreover, MCL1 inhibition, either alone or in combination with oth

114 rt the identification of fortilin as a novel MCL1-interacting protein by screening of a yeast two-hyb

115 uced apoptosis in response to an ablation of MCL1-L by meayamycin B.

116 s to examine selected membrane activities of MCL1 and BAK under apoptotic-like conditions.

117 OS stress also caused deglutathionylation of MCL1, followed by a rapid degradation of this cell survi

118 The degradation of MCL1 was blocked in patient-derived tumour cells that la

119 hase experiment showed that the depletion of MCL1 by siRNA-MCL1 was associated with the rapid degrada

120 ion strategy for the clinical development of MCL1 inhibitors.

121 ies are covered by the N-terminal domains of MCL1.

122 mage causes an increase in the expression of MCL1 along with increases in GADD45 and BAX and a decrea

123 Expression of MCL1 was found to increase upon exposure of ML-1 cells t

124 The increase in expression of MCL1 was further studied using a panel of human cell lin

125 EGFR signaling stimulates the expression of MCL1, an antiapoptotic protein, and a family of EGR tran

126 vealed that the BCL2-like structural fold of MCL1, but not that of BAK, forms stable heterodimeric co

127 cell survival because the truncated form of MCL1 (unlike those of BCL2 and BCLX) retained antiapopto

128 The N-terminally truncated form of MCL1 was expressed to varying extents in normal lymphoid

129 n, and the cell cycle regulatory function of MCL1 is mediated through its interaction with PCNA.

130 h high affinity to the BH3-binding groove of MCL1.

131 in CML cells, including the long isoform of MCL1, which proved to be essential for the antiapoptotic

132 The level of MCL1 protein was 5-fold elevated compared with ML-1 cell

133 correlated with increased protein levels of MCL1 and BCL2 target genes.

134 ent plasma cells expressed reduced levels of MCL1 relative to wild-type controls, and transgenic expr

135 , however, express abnormally high levels of MCL1, contributing to chemoresistance and disease relaps

136 addition, the intracellular localization of MCL1(Delta)(4A) was identical to that of wild type MCL1.

137 The mechanism of MCL1 overexpression in cancer is not well understood.

138 ly increased the electrophoretic mobility of MCL1 and differed from the phosphorylation/band shift to

139 es not alter the electrophoretic mobility of MCL1, and (ii) ERK-independent phosphorylation, which re

140 A mutant of MCL1 that lacks PCNA binding (MCL1(Delta)(4A)) could not

141 take assay showed that the overexpression of MCL1 significantly inhibited the cell cycle progression

142 hibiting amplification and overexpression of MCL1, indicate that such cells may exhibit increased sen

143 e of the normal, highly regulated pattern of MCL1 expression, in addition to providing a model for st

144 Phosphorylation of MCL1 directs its interaction with the tumour-suppressor

145 The polyubiquitylation of MCL1 then targets it for proteasomal degradation.

146 ch was found quite stable in the presence of MCL1.

147 teraction with the 3' untranslated region of MCL1 mRNA.

148 ary DNA containing only the coding region of MCL1 rescued H23 cells from the toxicity of a 3' untrans

149 t not a siRNA targeting the coding region of MCL1.

150 The up-regulation of MCL1 and EGR2 by EGF was further confirmed in osteoproge

151 Repression of MCL1 released the proapoptotic protein BAK from MCL1, an

152 Our data suggest the roles of MCL1 and ARID1A in BL pathogenesis and demonstrate that

153 be phenocopied by RNAi-mediated silencing of MCL1.

154 1 alternative exon and alter the splicing of MCL1 pre-mRNA.

155 ins were involved in alternative splicing of MCL1.

156 s T-ALL progression through stabilization of MCL1 and suggest that impeding this pathway has potentia

157 otes leukemogenesis by regulating stimuli of MCL1 expression.

158 IF4B results in reduced protein synthesis of MCL1, which, in turn, induces apoptotic cell death of ca

159 edominantly nuclear and identical to that of MCL1, as shown by immunostaining and confocal microscopy

160 t of tumour cell lines exhibit dependence on MCL1 expression for survival and this dependence is also

161 ty of these molecules for BCL2, BCL-X(L), or MCL1 has been established in vitro; whether they inhibit

162 On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establis

163 noma (HNSCC), up to 90% of which overexpress MCL1 and BCL-X(L).

164 osis at least in part through inhibiting p38-MCL1 pro-survival pathway.

165 hly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R.

166 was found to have amplified the prosurvival MCL1 gene (3-fold) and overexpressed the MCL1 protein.

167 overexpression of the antiapoptotic protein MCL1 was sufficient to circumvent apoptosis in this sett

168 CL1, which encodes the antiapoptotic protein MCL1, is among the most frequently amplified genes in hu

169 ncing stability of the antiapoptotic protein MCL1; therefore, IRAK inhibition reduced MCL1 stability

170 ve downregulation of the prosurvival protein MCL1.

171 Here we show that the pro-survival protein MCL1 is a crucial regulator of apoptosis triggered by an

172 ted with release of the pro-survival protein MCL1.

173 Myeloid cell leukemia 1 protein (MCL1) is an anti-apoptotic protein that is structurally

174 unctions by binding the BCL2 family proteins MCL1 and BFL1.

175 tic and molecular approach for the recurrent MCL1 amplicon at chromosome 1 in human tumor cells.

176 ein MCL1; therefore, IRAK inhibition reduced MCL1 stability and sensitized T-ALL to combination thera

177 Nuclear factors that regulate MCL1 transcription have now been identified, extending t

178 cin B up-regulated MCL1-S and down-regulated MCL1-L.

179 otting showed that meayamycin B up-regulated MCL1-S and down-regulated MCL1-L.

180 ptional and post-transcriptional regulation, MCL1 is subject to multiple, separate, post-translationa

181 In the acquired resistance setting, MCL1 suppression in response to HSP90 inhibitors is main

182 t showed that the depletion of MCL1 by siRNA-MCL1 was associated with the rapid degradation of fortil

183 the depletion of intracellular MCL1 by siRNA-MCL1 was associated with the significant reduction of th

184 how that the deubiquitinase USP9X stabilizes MCL1 and thereby promotes cell survival.

185 to occur within the 20S proteasome subunits, MCL1, RRM1, USP8, and CKAP5.

186 ein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylat

187 el is now presented, which demonstrates that MCL1 can undergo distinct phosphorylation events - media

188 gnostic value in this setting, we found that MCL1 overexpression does correlate with poor patient sur

189 emic blasts from AML patients and found that MCL1 transcripts were consistently expressed at high lev

190 from undergoing apoptosis, it is likely that MCL1, an anti-apoptotic protein inducible by growth and

191 These findings show that MCL1 can shape the makeup of the CD8(+) T cell response,

192 reagents and hemocyte monolayers showed that MCL1 functions as an antiadhesive protective coat becaus

193 This is important because it shows that MCL1 expression may be an important determinant of the f

194 in AML pathogenesis in mice and suggest that MCL1 may be a promising therapeutic target in patients w

195 These data suggest that MCL1, in addition to being an anti-apoptotic molecule, s

196 An in vitro pull-down assay suggested that MCL1 is the only Bcl-2 family protein to interact with P

197 ins with collagenous domains suggesting that MCL1 is a member of a patchily distributed gene family.

198 Here we show in vitro and in vivo that MCL1 interacts with the cell cycle regulator, proliferat

199 The MCL1 member of the BCL2 family is up-regulated during th

200 Functional investigations identified the MCL1 gene as a critical downstream effector for BET degr

201 phosphatase 1/2A inhibitors also induced the MCL1 band shift/phosphorylation.

202 catalyze dynamic histone acetylation of the MCL1 alternative exon and alter the splicing of MCL1 pre

203 red rapidly and was transient, levels of the MCL1 mRNA being elevated within 4 h and having returned

204 ation events to regulate the turnover of the MCL1 protein and thus its availability for antiapoptotic

205 hese results indicate that expression of the MCL1 viability-enhancing gene is regulated through a cyt

206 val MCL1 gene (3-fold) and overexpressed the MCL1 protein.

207 Thus, MCL1 undergoes two distinct types of phosphorylation: (i

208 nt mutant of fortilin lacking the binding to MCL1, was significantly shorter than that of wild-type f

209 high BCL-xL expression confers resistance to MCL1 repression, thereby identifying a patient-selection

210 Taken together, MCL1 is a regulator of both apoptosis and cell cycle pro

211 These results point towards MCL1 as a target for the treatment of a wide range of tu

212 ycle progression as effectively as wild type MCL1.

213 elta)(4A) was identical to that of wild type MCL1.

214 diminishes the antiapoptotic, long variant (MCL1-L).

215 of the proapoptotic, short splicing variant (MCL1-S) and diminishes the antiapoptotic, long variant (

216 s, in stroma contact models, and in vivo via MCL1 reduction and by effector caspase activation.

217 s finding prompted us to investigate whether MCL1, in addition to its anti-apoptotic function, has an

218 However, while MCL1 phosphorylation induced by the protein kinase C act

219 ed with nascent pre-mRNA in general and with MCL1 pre-mRNA specifically.

220 gnosis of human NSCLC is not associated with MCL1, despite its overexpression in many NSCLCs.

221 Fortilin specifically interacted with MCL1 both in vitro and in vivo.

222 screening of a yeast two-hybrid library with MCL1 as bait.