ライフサイエンスコーパス: MTAP

1 MTAP differs from previous attempts at regulatory motif

2 MTAP encodes the enzyme methylthioadenosine phosphorylas

3 MTAP expression causes a significant decrease in intrace

4 MTAP expression does not affect the growth rate of cells

5 MTAP is a ubiquitously expressed homotrimeric-subunit en

6 MTAP is abundant in normal cells but is deficient in man

7 MTAP is frequently lost due to its proximity to the comm

8 MTAP presents a new approach to the challenging problem

9 MTAP(+) normal keratinocytes and pancreatic carcinoma li

10 MTAP(-) T-ALL-derived cell line, CEM cells were very sen

11 MTAP-deleted cells accumulate the metabolite methylthioa

12 MTAP-negative A549 lung cancer cells were transfected wi

13 te methylthioribosyltransferase, EC 24.2.28; MTAP) plays a role in purine and polyamine metabolism an

14 or in combination with a salvage agent as a MTAP-selective therapy and therefore lay the foundation

15 Mice homozygous for a MTAP null allele (Mtap(lacZ)) have an embryonic lethal p

16 L-alanosine can be increased by the use of a MTAP substrate, which protects MTAP+ normal cells.

17 A is effective for in vivo treatment of A549 MTAP(-/-) and H358 MTAP(+/+) tumors.

18 In addition, MTAP-expressing cells are suppressed for tumor formation

19 action certain antifolates may have against MTAP-deficient malignancies.

20 and dysregulated alternative splicing of all MTAP isoforms.

21 al role in tumorigenesis, we have created an MTAP-knockout mouse.

22 Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence.

23 r in MCF7, a breast cancer cell line with an MTAP gene deletion.

24 wth of both MTAP(+) (Molt-4 and Molt-16) and MTAP(-) (CEM and HSB2) cell lines.

25 ons of 9p21 that inactivate CDKN2A, ARF, and MTAP are common in a wide variety of human cancers.

26 Furthermore, normal lymphocytes and MTAP+ primary T-ALL cells were rescued from L-alanosine

27 st gene flanking each side being MIR31HG and MTAP, neither of which has been implicated in BMD or BMC

28 tend to have reduced levels of Mtap mRNA and MTAP protein in addition to unaltered levels of methylde

29 16 tumor suppressor gene (2 of 7 tumors) and MTAP gene (3 of 7).

30 which can physically interact with archetype MTAP, have been identified.

31 Approximately 15% of human cancers are MTAP(-/-).

32 inhibitor of de novo AMP synthesis, than are MTAP+ primary T-ALL cells.

33 tion of point mutations with cancer, such as MTAP and MAGED1.

34 Because MTAP phosphorolyzes 5'-deoxy-5'-methylthioadenosine (MTA

35 samples showed a frequent breakpoint between MTAP exon 4 and exon 5.

36 xobutanoic acid represses ODC levels in both MTAP-deleted yeast and human tumor cell lines, indicatin

37 AMP synthesis, inhibited the growth of both MTAP(+) (Molt-4 and Molt-16) and MTAP(-) (CEM and HSB2)

38 by the MTAP substrate 5'-deoxyadenosine, but MTAP-T-ALL cells were not.

39 of 5'-methylthioadenosine (MTA) catalyzed by MTAP and were corrected for the forward commitment to ca

40 hioadenosine (MTA, the metabolite cleaved by MTAP) in cells harboring MTAP deletions.

41 Six distinct retroviral-sequence-containing MTAP isoforms, each of which can physically interact wit

42 In contrast, MTAP(-) cell lines, which cannot recycle purines from en

43 t of six samples with intact p16 but deleted MTAP locus.

44 ee of the four cell lines lacking detectable MTAP protein were unable to grow in Hcy-containing media

45 r hypermethylation was shown to downregulate MTAP expression and may represent a mechanism of MTAP in

46 sible alterations of p53, PTEN, K-ras, EGFR, MTAP, and p16 (MTS1/CDKN2) genes.

47 ccharomyces cerevisiae the MEU1 gene encodes MTAP and that Meu1delta cells have an 8-fold increase in

48 The gene encoding MTAP, MTAP, is frequently codeleted along with the tumor

49 with eukaryotic expression vectors encoding MTAP cDNA in sense and antisense orientations.

50 that, in addition to deletion of the entire MTAP gene, a common break point was between exons 4 and

51 hionine depletion than were cells expressing MTAP protein (sense transfectoma).

52 se, and this flux increases 2-fold following MTAP deletion.

53 9p is uncertain, and the molecular basis for MTAP deficiency in cancer is unknown.

54 s that have an identical genotype except for MTAP status.

55 e may be selection in early stages of MF for MTAP deletion within the cutaneous tumor microenvironmen

56 nhibitors are the most powerful reported for MTAP and have sufficient affinity to be useful in inhibi

57 the tightest binding inhibitor reported for MTAP.

58 sine (2AMTA) as an alternative substrate for MTAP and MTAN enzymes.

59 her investigation as a potential therapy for MTAP/CDKN2A-deleted tumors.

60 enosine, is a highly selective treatment for MTAP-negative cancers.

61 referential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-

62 SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two ext

63 ified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, and ZNF668) in which NM/SSM-specifi

64 ed overexpression of metabolism-related gene MTAP (methylthioadenosine phosphorylase) in SSM resulted

65 in vivo treatment of A549 MTAP(-/-) and H358 MTAP(+/+) tumors.

66 tabolite cleaved by MTAP) in cells harboring MTAP deletions.

67 ese data show a high frequency of homozygous MTAP deletions in NSCLC which is associated with detecta

68 Human MTAP is characterized by a late S(N)1 transition state w

69 s for the proposed transition state of human MTAP on the basis of the known ribooxacarbenium characte

70 The X-ray crystal structure of human MTAP with bound MT-Imm-A also reveals that the 5'-methyl

71 Interaction of 2AMTA with human MTAP was also characterized by pre-steady-state kinetics

72 We kinetically characterize 2AMTA with human MTAP, bacterial MTANs and use 2,6-diaminopurine as a flu

73 Thus, MTA accumulation in MTAP-deleted cancers creates a hypomorphic PRMT5 state t

74 Of 23 malignant cell lines deficient in MTAP protein, all but one had complete or partial deleti

75 ne putrescine stimulates colony formation in MTAP-expressing cells.

76 Expression of MTAP in MTAP-deleted MCF-7 breast adenocarcinoma cells results i

77 Deletion of MTAP in MTAP-proficient cells rendered them sensitive to PRMT5 d

78 e identified strongly associated variants in MTAP, a gene adjacent to the familial melanoma susceptib

79 d cells with MT-DADMe-ImmA and MTA inhibited MTAP, increased cellular MTA concentrations, decreased p

80 However, when we introduced MTAP cDNA into MTAP-deficient MCF-7 cells, the resulting cell line was

81 e that normal cells, which are intrinsically MTAP+, would be protected from L.-alanosine toxicity, wh

82 However, when we introduced MTAP cDNA into MTAP-deficient MCF-7 cells, the resulting

83 ull cancer cell lines compared with isogenic MTAP-expressing counterparts.

84 In this work, we propose a method (MTAP) that substantially reduces the effort required to

85 Importantly, in early stage MF, MTAP loss occurred independently of CDKN2A loss in 37% o

86 The gene encoding MTAP, MTAP, is frequently codeleted along with the tumor suppr

87 struct (antisense transfectoma) expressed no MTAP protein and were more sensitive to both purine and

88 hesized and evaluated a potentially nontoxic MTAP substrate, 9-beta-D-erythrofuranosyladenine (EFA).

89 have only been tested in naturally occurring MTAP-positive and -negative cell lines, which might have

90 e other hand, the IC50 for 60% (12 of 20) of MTAP+ primary T-ALL was 19+/-18 microM (range, 1.7-67 mi

91 se chain reaction amplification of exon 8 of MTAP showed a deletion in 16 of 48 (33.3%) patients at d

92 luoromethylornithine inhibits the ability of MTAP-deficient cells to form colonies in soft agar, wher

93 s to be because of the enzymatic activity of MTAP, as a protein with a missense mutation in the activ

94 The finding of frequent deficiency of MTAP in T-ALL offers the possibility of an enzyme target

95 Deletion of MTAP in MTAP-proficient cells rendered them sensitive to

96 Homozygous deletions of MTAP exon 8 could be detected in 19 of 50 NSCLC samples

97 putative salvage pathway genes downstream of MTAP also cause elevated ODC activity and elevated polya

98 y marks the first report of the existence of MTAP in any bacterium.

99 Expression of MTAP in MTAP-deleted MCF-7 breast adenocarcinoma cells r

100 The sole function of MTAP is to recycle 5'-methylthioadenosine (MTA) to S-ade

101 The function of MTAP is to salvage methylthioadenosine, which is produce

102 adenosine (MTA) was blocked by inhibition of MTAP with methylthio-DADMe-Immucillin-A (MTDIA), an oral

103 hree-transition-state analogue inhibitors of MTAP and MTAN.

104 DKN2A occurred in 18% of samples but loss of MTAP alone was uncommon.

105 To determine if loss of MTAP plays a functional role in tumorigenesis, we have c

106 expression and may represent a mechanism of MTAP inactivation.

107 e clone containing a processed pseudogene of MTAP.

108 Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 depend

109 The specific role of MTAP in cutaneous T-cell lymphoma subgroups, mycosis fun

110 Deep sequencing of MTAP/CDKN2A-CDKN2B loci in 77 peripheral blood mononucle

111 ion of methylthioadenosine, the substrate of MTAP, protected the MTAP(+) cells but not the MTAP(-) ce

112 The most current version of MTAP can be downloaded from http://biobase.ist.unomaha.e

113 line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of

114 trials for the treatment of T-ALL and other MTAP-deficient malignancies with L-alanosine.

115 ase adenine, loss of this pathway in p16(-), MTAP(-) cells might sensitize these cells to methotrexat

116 pancreatic carcinoma cell lines were p16(-), MTAP was codeleted in all five cases.

117 ifolates such as methotrexate than are p16+, MTAP+ cells.

118 e gene order on chromosome 9p2l is p15, p16, MTAP, IFNA, and interferon beta gene (IFNB).

119 p16-, MTAP- malignant cells have been shown to be more suscept

120 we reintroduced MTAP activity into two p16-, MTAP- cell model systems, the MiaPaCa-2 and PANC-1 human

121 5'-Methylthioadenosine phosphorylase (MTAP) and 5'-methylthioadenosine nucleosidase (MTAN) cat

122 -deoxy-5'-methylthioadenosine phosphorylase (MTAP) and the genes of the IFN-alpha and -beta cluster (

123 Methylthioadenosine phosphorylase (MTAP) and the tumor suppressor genes CDKN2A-CDKN2B are f

124 ied as 5'-methylthioadenosine phosphorylase (MTAP) based on its biochemical properties and mass spect

125 he enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine

126 The human methylthioadenosine phosphorylase (MTAP) gene is located on 9p21 and is frequently homozygo

127 enzyme 5'-methylthioadenosine phosphorylase (MTAP) has been implicated as both a cancer target and a

128 ciency of methylthioadenosine phosphorylase (MTAP) in T-cell acute lymphoblastic leukemia (T-ALL) and

129 5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway.

130 Human methylthioadenosine phosphorylase (MTAP) is a purine and methionine metabolic enzyme presen

131 Methylthioadenosine phosphorylase (MTAP) is an important enzyme for the salvage of adenine

132 -Deoxy-5'-methylthioadenosine phosphorylase (MTAP) is involved in the salvage of adenine and methylth

133 ession of methylthioadenosine phosphorylase (MTAP), a key enzyme in the salvage pathway.

134 Methylthioadenosine phosphorylase (MTAP), an enzyme essential for the salvage of adenine an

135 Methylthioadenosine phosphorylase (MTAP), an enzyme involved in purine and methionine metab

136 ciency of methylthioadenosine phosphorylase (MTAP), both located on chromosome 9p21, have been indepe

137 ay enzyme methylthioadenosine phosphorylase (MTAP), frequently deleted in cancer, affects methionine

138 encoding methylthioadenosine phosphorylase (MTAP), the initial enzyme in the methionine salvage path

139 ping gene methylthioadenosine phosphorylase (MTAP).

140 ion of 5'-methylthioadenosine phosphorylase (MTAP).

141 human 5'-methylthioadenosine phosphorylase (MTAP).

142 human 5'-methylthioadenosine phosphorylase (MTAP).

143 Methythioadenosine phosphorylase (MTAP) functions solely in the polyamine pathway of mamma

144 yme methylthioadenosine (MTA) phosphorylase (MTAP) in 36% of lines, transcription factor DMRTA1 (27%)

145 encoding methylthioadenosine phosphorylase, MTAP.

146 ancer genes, including deletions in PPP2R2A, MTAP and MAP2K4.

147 EFA at 20 microM or less rescued primary MTAP+ T-ALL cells and normal lymphocytes from L-alanosin

148 the use of a MTAP substrate, which protects MTAP+ normal cells.

149 MTAP copy number loss (P < 0.01) but reduced MTAP expression was also detected in the absence of copy

150 In CD4(+) cells from SS, reduced MTAP mRNA expression correlated with MTAP copy number lo

151 We have reintroduced MTAP into MCF-7 breast adenocarcinoma cells and have exa

152 nd the underlying mechanism, we reintroduced MTAP activity into two p16-, MTAP- cell model systems, t

153 The remainder can be rendered MTAP(-) through MTAP inhibitors.

154 AP-dependent adenine salvage pathway renders MTAP+ cells less dependent on de novo purine synthesis a

155 In addition, EFA selectively rescued MTAP+ MOLT-4 cells from L-alanosine toxicity at 25 micro

156 that EFA is an effective agent for salvaging MTAP+ cells from L-alanosine toxicity and is superior to

157 ne incorporation, DNA synthesis in all seven MTAP-primary T-ALL cells was inhibited by L-alanosine wi

158 Since MTAP substrates MTA and 5'deoxyadenosine are prone to to

159 0 loci (TYR, AFG3L1P, CDK10, MYH7B, SLC45A2, MTAP, ATM, CLPTM1L, FTO, and CASP8) that have previously

160 n 213 skin samples from patients with MF/SS, MTAP copy number loss (34%) was more frequent than CDKN2

161 IA antitumor activity in xenografts supports MTAP as a target for lung cancer therapy.

162 indings suggest the possibility of targeting MTAP for selective therapy of T-ALL.

163 ne synthesis and hence less susceptible than MTAP- malignant cells to the growth-inhibitory actions o

164 We demonstrate that MTAP- T-ALL cells obtained at relapse are as sensitive t

165 These results indicate that MTAP deficiency in cancer is primarily due to codeletion

166 These results indicate that MTAP has tumor suppressor activity and suggest that its

167 These results prove that MTAP deficiency contributes directly to the sensitivity

168 We now report that MTAP-primary T-ALL cells are more sensitive to the toxic

169 late polyamine biosynthesis and suggest that MTAP deletion may lead to ODC activation in human tumors

170 sic KIEs (1'-(14)C and 9-(15)N) suggest that MTAP has a dissociative S(N)1 transition state with its

171 The MTAP gene consists of eight exons and seven introns.

172 The MTAP gene is frequently deleted in human cancers because

173 Because the MTAP gene is located adjacent to the tumor-suppressor ge

174 from endogenously generated MTA, because the MTAP inhibitor 5'-chloro-5'-de- oxyformycin A potentiate

175 fection with MTAP cDNA (i) restored both the MTAP-dependent adenine and methionine salvage pathways,

176 ere rescued from L-alanosine toxicity by the MTAP substrate 5'-deoxyadenosine, but MTAP-T-ALL cells w

177 We have cloned the MTAP gene, and have constructed a topologic map of the 9

178 cally interacts with the CDKN2A/B locus, the MTAP gene and an interval downstream of IFNA21.

179 TAP, protected the MTAP(+) cells but not the MTAP(-) cells from alanosine toxicity.

180 cancer is primarily due to codeletion of the MTAP and p16 genes.

181 the p16 gene, we examined the status of the MTAP gene in T-ALL patients.

182 Partial or total deletions of the MTAP gene were found in primary T-cell acute lymphoblast

183 However, the order of the MTAP, p16, p15, and IFNA genes on chromosome 9p is uncer

184 support the hypothesis that operation of the MTAP-dependent adenine salvage pathway renders MTAP+ cel

185 Hcy-containing media, whereas all six of the MTAP-positive cell lines tested showed strong growth.

186 nosine, the substrate of MTAP, protected the MTAP(+) cells but not the MTAP(-) cells from alanosine t

187 Previously, we reported that the MTAP gene was deleted in over 30% of T-ALL patients at b

188 Thus the MTAP loss in malignant cells may be an example of gene d

189 The sequence is 92% homologous to the MTAP cDNA, is flanked at its 3' end by a repetitive elem

190 This may be in part due to the MTAP-dependent salvage of adenine moieties from endogeno

191 Intriguingly, two of these MTAP exons arose from early and independent retroviral-i

192 e antipurine actions of MTX in some of these MTAP(+) lines.

193 he remainder can be rendered MTAP(-) through MTAP inhibitors.

194 10(-14) for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 x 10(-7) for rs702332

195 hionine uptake, with no major changes due to MTAP deletion.

196 fic for p16INK4A exon 3, the exon nearest to MTAP exon 8.

197 cells may be exploited to selectively treat MTAP-negative cancers by inhibiting de novo purine synth

198 arm of human chromosome 9 at band p21, where MTAP and interferon alpha genes (IFNA) also map.

199 rotected from L.-alanosine toxicity, whereas MTAP-tumor cells would be killed.

200 morigenesis is well established, but whether MTAP loss directly affects tumorigenesis is unclear.

201 is suggested focal deletions consistent with MTAP and CDKN2A copy number loss detected with quantitat

202 reduced MTAP mRNA expression correlated with MTAP copy number loss (P < 0.01) but reduced MTAP expres

203 We further investigated the ten samples with MTAP deletions but intact p16INK4A exon 1alpha with prim

204 at formed an in frame fusion transcript with MTAP in a glioma xenograft, and that is homozygously del

205 It was found that transfection with MTAP cDNA (i) restored both the MTAP-dependent adenine a

206 c carcinoma cell lines, by transfection with MTAP cDNA.