ライフサイエンスコーパス: HTRA1

1 ta1 signalling through the secreted protease HTRA1.

2 e of human ovarian tumors with downregulated HtrA1.

3 ls, resulting in autocatalytic activation of HtrA1.

4 selectively cleaved by the human recombinant HTRA1.

5 ned medium with or without human recombinant HTRA1.

6 the alginate cultures overexpressing active HtrA1.

7 little is known about the function of human HtrA1.

8 in limited autoproteolysis and activation of HtrA1.

9 cts serine protease activity associated with HtrA1.

10 We report here that HtrA1, a candidate tumor suppressor, is downregulated in

11 otide polymorphism in the promoter region of HTRA1, a serine protease gene on chromosome 10q26, is a

12 One of the up-regulated proteins, HtrA1, a serine protease, was detected at high levels in

13 Furthermore, HTRA1 mRNA and HTRA1 activity are up-regulated in response to elevated

14 f aggrecan by HtrA1 was strongly enhanced by HtrA1 agonists such as CPII, a C-terminal hexapeptide de

15 HumHtrA2 is also homologous to human HtrA1, also known as L56/HtrA, which is differentially e

16 re we provide evidence that decidua-secreted HtrA1 and HtrA3 antagonize HtrA4-mediated trophoblast in

17 by HtrA1 or HtrA3 knockdown, supporting that HtrA1 and HtrA3 are crucial for trophoblast-decidual cel

18 Specifically, HtrA1 and HtrA3 expression is up-regulated under decidua

19 In contrast, both HtrA1 and HtrA3 have been shown to inhibit trophoblast i

20 We demonstrated that HtrA1 and HtrA3 interact with and degrade HtrA4 and ther

21 he interaction between ARMS2 and smoking and HTRA1 and smoking, after adjustment for CFH and age.

22 HTRA1 and the predicted LOC387715/ARMS2 gene were both t

23 61170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3), using TaqMan SNP genotyping

24 61170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3; P>0.35).

25 Although specific alleles for CFH, ARMS2, HTRA1, and C3 may predict the development of AMD, they d

26 rmed for the genes CCR3, CFH, CX3CR1, ERCC6, HTRA1, and VEGF.

27 MD patients were strongly immunolabeled with HTRA1 antibody.

28 oteolysis and a reduced affinity for an anti-HtrA1 antibody.

29 CFH, C3, C2, and ARMS2/HTRA1 are associated with large drusen and advanced AMD.

30 lternative complement pathway, and LOC387715/HtrA1 are the most consistent genetic risk factors for a

31 The significant associations in ARMS2 and HTRA1 are with polymorphisms in strong LD that confer vi

32 e polymorphisms (SNPs) at the CFH, FZD4, and HTRA1/ARMS2 loci were tested for replication.

33 The SNP rs10490924 in HTRA1/ARMS2 showed a borderline association with respons

34 These observations raise the possibility of HtrA1 as a candidate tumor suppressor involved in promot

35 h cartilage from healthy joints, implicating HtrA1 as a critical protease involved in proteoglycan tu

36 We previously identified serine protease HtrA1 as a downregulated gene in epithelial ovarian canc

37 results offer an original identification of HtrA1 as a microtubule-associated protein and provide in

38 The potential role of HtrA1 as a predictive factor of clinical response to che

39 We have previously identified HTRA1 as being up-regulated in osteoarthritic patients a

40 This activity is specific to HtrA1, as similar assays with HtrA2 showed minimal ApoE4

41 Purified HtrA1 associates with purified alpha- and beta-tubulins,

42 Downregulation of HtrA1 attenuated cisplatin- and paclitaxel-induced cytot

43 Here, we report that loss of HtrA1 attenuates anoikis--a critical physiologic barrier

44 ell motility, whereas enhanced expression of HtrA1 attenuates cell motility.

45 established that, like the human orthologue HtrA1, BbHtrA is proteolytically active against numerous

46 HtrA1 belongs to a family of serine proteases found in o

47 expression of a catalytically active form of HtrA1, but not an active site mutant (S328A), caused a m

48 he presence of risk alleles for CFH, ARMS 2, HTRA1, C3, or TLR3.

49 leotide polymorphisms in 7 genes (CFH, ARMS2/HTRA1, CFB, C2, C3, CFI, and LIPC) were genotyped.

50 pitope sequence (VQTV(356)) generated at the HtrA1 cleavage site was developed.

51 Recombinant HTRA1 cleaves RPE-secreted proteins involved in regulati

52 ture requirement A serine peptidase 1 (ARMS2/HTRA1), complement component 2 (C2), complement factor B

53 These findings suggest a link between HTRA1, complement regulation, and amyloid deposition in

54 Moreover, HtrA1 cosediments and copurifies with microtubules.

55 protease concentrations, is prevented under HtrA1-deficient conditions as well as by CARASIL mutatio

56 Bacterial HtrA1 (DegP) is a heat shock-induced protein that behave

57 We show here that human HTRA1 degrades aggregated and fibrillar tau, a protein t

58 ced cytotoxicity, while forced expression of HtrA1 enhanced cisplatin- and paclitaxel-induced cytotox

59 nnot be used to determine how abnormal ARMS2/HTRA1 expression can initiate RPE pathology.

60 mplete absence or markedly reduced levels of HtrA1 expression compared to the brushings of ovarian su

61 HTRA1 expression in genotyped RPE cells was determined b

62 HtrA1 expression was upregulated by both cisplatin and p

63 In response to loss of anchorage, HtrA1 expression was upregulated in SKOV3 cells, resulti

64 ate compared with those with lower levels of HtrA1 expression.

65 cell death, whereas protease-inactive mutant HtrA1 failed to result in either the inhibition of EGFR/

66 study, the authors focused on a substrate of HTRA1, fibronectin, because fibronectin fragments (Fnfs)

67 ing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis

68 Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, in

69 The HTRA1 gene encodes a secreted serine protease.

70 e polymorphism in the promoter region of the HTRA1 gene, as has previously been suggested.

71 Western blot analysis demonstrated that HtrA1-generated aggrecan fragments containing the VQTV(3

72 ith polymorphisms in the LOC387715/ARMS2 and HTRA1 genes on 10q26.

73 linked genome-wide association studies ARMS2/HTRA1 genes, located at the chromosome 10q26 locus, are

74 ified CFH, C2, C3, CFB, CFI, APOE, and ARMS2/HTRA1 genes/regions and the novel genes LIPC, CETP, and

75 HtrA1 has also been reported to cleave the tau protein (

76 HTRA1 has the capacity to degrade numerous extracellular

77 s sequence homology to human serine protease HtrA1 (hHtrA1).

78 MD, including two donors with the rare ARMS2/HTRA1 homozygous genotype.

79 sk of incident GA among those with the ARMS2/HTRA1 homozygous risk genotype (hazard ratio [HR] Q5 vs

80 2 (age-related maculopathy susceptibility 2)-HTRA1 (HtrA serine peptidase 1) (P =2.7 x 10(-72)), CFH

81 Mtb) has three putative HtrA-like proteases, HtrA1, HtrA2, and HtrA3.

82 the predicted tumor stroma-specific markers HTRA1, HTRA3, MXRA5, MXRA8, and SERPING1 in situ.

83 To define the role of the serine protease HTRA1 in age-related macular degeneration (AMD) by exami

84 However, the precise role of HTRA1 in AMD remains elusive.

85 ether, these findings support a key role for HTRA1 in AMD susceptibility and identify a potential new

86 ), but the functional consequence of loss of HtrA1 in EOC remains largely unclear.

87 By transgenically expressing human HTRA1 in mouse retinal pigment epithelium, we showed tha

88 s in our understanding of the role played by HTRA1 in musculoskeletal pathology.

89 However, the function of HTRA1 in other closely related musculoskeletal diseases

90 endent growth, while exogenous expression of HtrA1 in OV202 induces cell death.

91 nduced cytotoxicity and suggest that loss of HtrA1 in ovarian and gastric cancers may contribute to i

92 diated cell death and that downregulation of HtrA1 in ovarian cancer may contribute to malignant phen

93 eveal for the first time a novel function of HtrA1 in promoting anoikis by attenuating activation of

94 Stable knockdown of HtrA1 in SKOV3 and TOV21G cells resulted in resistance t

95 Downregulation of HtrA1 in SKOV3 by antisense transfection promotes anchor

96 skin fibroblasts for a facilitating role of HtrA1 in TGF-beta pathway activation.

97 d these studies and investigated the role of HTRA1 in the pathogenesis of intervertebral disc (IVD) d

98 now exist to support a detrimental role for HTRA1 in the pathogenesis of joint and intervertebral di

99 nitial mechanistic insights into the role of HtrA1 in the regulation of cell motility by modulating m

100 pigment epithelium, we showed that increased HTRA1 induced cardinal features of PCV, including branch

101 Recombinant HTRA1 induced MMP production in IVD cell cultures throug

102 HtrA1-induced cell death is not inhibited by the broad c

103 HTRA1-induced fibronectin proteolysis resulted in the ge

104 Active HtrA1 induces cell death in a serine protease-dependent

105 uspended SKOV3 cells, enhanced expression of HtrA1 inhibited EGFR/AKT pathway, leading to increased c

106 and immunofluorescence assays revealed that HtrA1 interacted with EGFR not only on the cell membrane

107 Human HTRA1 is a highly conserved secreted serine protease tha

108 ere, we report the first evidence that human HtrA1 is a microtubule-associated protein and modulates

109 ound in the nervous system, demonstrate that HtrA1 is an allele-selective ApoE-degrading enzyme that

110 Expression of HtrA1 is downregulated in five of seven ovarian cancer c

111 es, and neuritic plaques, respectively, when HTRA1 is expressed at elevated levels.

112 Intracellular HtrA1 is localized to microtubules in a PDZ (PSD95, Dlg,

113 These data suggest that HTRA1 is performing regulated proteolysis during protein

114 Our results indicate that increased HTRA1 is sufficient to cause PCV and is a significant ri

115 phism, rs11200638, in the promoter region of HTRA1 is the most likely causal variant for AMD at 10q26

116 High temperature requirement protein A1 (HtrA1) is a primarily secreted serine protease involved

117 -temperature requirement serine protease A1 (HTRA1) is one of four known proteases belonging to the b

118 based on the methylation of 3 genes (CACNB2, HTRA1, KLF4) identified a poorer-outcome patient subset.

119 ors, which are most exaggerated in the ARMS2/HTRA1 lines.

120 In contrast to bacterial HtrA1, little is known about the function of human HtrA1

121 nd a locus on chromosome 10 encompassing the HTRA1/LOC387715/ARMS2 genes.

122 f genetic variation at the CFH and LOC387715/HTRA1 loci and smoking, the effect remained significant

123 ficant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3

124 f genetic risk, in addition to the LOC387715/HTRA1 locus and other environmental influences.

125 analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD

126 of an allele at microsatellite markers near htrA1 locus on 10q26.

127 ssociation of the rs3750846 SNP at the ARMS2/HTRA1 locus with subretinal/sub-retinal pigment epitheli

128 The association of the SNP at the ARMS2/HTRA1 locus with subretinal/sub-RPE hemorrhage and poore

129 on of TGF-beta signaling caused by a lack of HtrA1-mediated LTBP-1 processing as mechanism underlying

130 be a novel pathway by which serine protease HtrA1 mediates paclitaxel- and cisplatin-induced cytotox

131 Senescent HTRA1 mice developed occult CNV, which likely resulted f

132 In addition, HTRA1 mice displayed retinal pigment epithelium atrophy

133 of pro-invasive and pro-angiogenic mediators HTRA1, MMP1, FAM3C, PDGFA, and ADAM10.

134 Furthermore, HTRA1 mRNA and HTRA1 activity are up-regulated in respon

135 ssociated with elevated expression levels of HTRA1 mRNA and protein.

136 activity in three different cell lines, and HTRA1 mRNA expression exhibits no significant change bet

137 HTRA1 mRNA expression was significantly elevated in dege

138 HTRA1 mRNA levels were threefold higher in primary RPE c

139 of GA among those with the homozygous ARMS2/HTRA1 nonrisk genotype (HR, 1.0; P = 0.90).

140 JAR cell invasion, which can be reversed by HtrA1 or HtrA3 knockdown, supporting that HtrA1 and HtrA

141 ess HtrA4-expressing JAR cell invasion in an HtrA1- or HtrA3-dependent manner.

142 -H3, DEL-1, vitronectin, and serine protease HtrA1 (P < 0.01).

143 onstrate, by evaluating 45 tag SNPs spanning HTRA1, PLEKHA1, and predicted gene LOC387715/ARMS2, that

144 functional analyses, the disease-associated HTRA1 polymorphism resulted in a 2-fold increase in gene

145 rs11200638 SNP has no significant impact on HTRA1 promoter activity in three different cell lines, a

146 gher in primary RPE cells homozygous for the HTRA1 promoter risk allele than in RPE cells with the wi

147 A (homozygote risk) genotype at rs11200638 - HTRA1 promoter SNP (P = 0.001) and GG (homozygote risk)

148 The HTRA1 promoter SNP (rs11200638) and A69S at LOC387715/AR

149 Finally, downregulation of HtrA1 promotes cell motility, whereas enhanced expressio

150 esults therefore support a scenario in which HTRA1 promotes IVD degeneration through the proteolytic

151 In vitro, purified HtrA1 promotes microtubule assembly.

152 ed cell death, suggesting the requirement of HtrA1 protease activity in regulating anoikis.

153 ssue extracts identified the serine protease HtrA1/PRSS11 as a major protein component of human artic

154 ative or recombinant aggrecan with wild type HtrA1 resulted in distinct cleavage of these substrates.

155 ulins, and immunoprecipitation of endogenous HtrA1 results in coprecipitation of alpha-, beta-, and g

156 o two other HtrA proteases, E. coli DegP and HtrA1, revealed that all three HtrA proteases were rever

157 ARMS2/HTRA1 risk alleles decrease SOD2 defense, making RPE mor

158 donor eyes and screened for CFH, ARMS2, and HTRA1 risk genotypes by using an allele-discrimination a

159 l loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB

160 3766404, rs1061170, rs2274700 and rs393955), HTRA1 (rs11200638), CFHR1-5 (rs10922153, rs16840639, rs6

161 enotyping was performed for CFH (rs1061170), HTRA1 (rs1200638), and C3 (rs2230199).

162 They reduced HtrA1's abilities to associate with IGF-1 and to amelior

163 translation rate and appeared to compromise HtrA1's conformation and function.

164 sociated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) bi

165 which translated into a twofold increase in HTRA1 secretion by RPE cells with the risk genotype.

166 nfirmed these effects to be primarily due to HTRA1 serine protease activity.

167 r gastric tumors expressing higher levels of HtrA1 showed a higher response rate compared with those

168 Most importantly, downregulation of HtrA1 significantly enhanced the peritoneal disseminatio

169 le nucleotide polymorphism (SNP) rs10490924, HTRA1 SNPs rs11200638 and rs3793917, and CFH SNPs rs3939

170 , the identification of ApoE4 as an in vitro HtrA1 substrate suggests a potential biochemical mechani

171 Potential HTRA1 substrates were identified by incubating RPE-condi

172 A novel HtrA1-susceptible cleavage site within the interglobular

173 ator of TGF-beta bioavailability, as a novel HtrA1 target.

174 AMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to

175 variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular a

176 unctional studies have shown a mechanism for HTRA1 to instigate ocular tissue abnormalities.

177 ve linked a multifunctional serine protease, HTRA1, to AMD.

178 in and was also found to be increased within HTRA1-treated IVD cell cultures as well as in disc tissu

179 vage of chondroadherin at this site and that HTRA1 was indeed the only protease capable.

180 effect for both smoking with ARMS2 and with HTRA1 was not statistically significant.

181 Cleavage of aggrecan by HtrA1 was strongly enhanced by HtrA1 agonists such as CP

182 igh-temperature requirement serine protease (HTRA1) was identified as a candidate age-related macular

183 CFH, C3, C2, and ARMS2/HTRA1 were associated with large drusen and advanced AMD

184 The genes CFH, C3, CFB, and ARMS2/HTRA1 were associated with progression from intermediate

185 ased protein levels of the processed form of HTRA1 were demonstrated in degenerate disc tissues via i

186 Two SNPs in ARMS2 and HTRA1 were genotyped in 685 cases and 269 controls by a

187 ne variant within LOC387715/ARMS2 and one in HTRA1 were significantly associated with affected status

188 enoid lesions in rhesus monkeys in ARMS2 and HTRA1 were similar in frequency between the two phenotyp

189 temperature requirement serine peptidase A1 (HtrA1), which is found in the nervous system, demonstrat

190 Here we show that expression of HtrA1, which is frequently downregulated in ovarian canc

191 cluding Hsp110, Hsp70, and Hsp40, as well as HtrA1, which might be harnessed to reverse deleterious p