ライフサイエンスコーパス: prelamin A

1 on 11 of LMNA (the gene encoding lamin C and prelamin A).

2 TE24, leading to an accumulation of farnesyl-prelamin A.

3 show that HIV-PIs caused an accumulation of prelamin A.

4 s a deletion of 50 aa near the C terminus of prelamin A.

5 A and leads to the accumulation of farnesyl-prelamin A.

6 ctive processing and nuclear accumulation of prelamin A.

7 that result in the deletion of 50 aa within prelamin A.

8 g mice lacking the farnesylated CAAX protein prelamin A.

9 rf, that binds the carboxyl-terminal tail of prelamin A.

10 xyl-terminal 18 amino acid residues of human prelamin A.

11 to the presence of permanently farnesylated prelamin A.

12 ulation of farnesylated, membrane-associated prelamin A.

13 leavage sites from amphibian, bird, and fish prelamin A.

14 ), where all of the lamin A is produced from prelamin A.

15 A processing, leading to the accumulation of prelamin A.

16 lead to an accumulation of non-farnesylated prelamin A.

17 its ZMPSTE24 and leads to an accumulation of prelamin A.

18 biogenesis and leading to an accumulation of prelamin A.

19 the accumulation of the farnesylated form of prelamin A.

20 abolished when the miR-9-binding site in the prelamin A 3' UTR was mutated.

21 ZMPSTE24 processes prelamin A, a component of the nuclear lamina intermedia

22 In animals, Ste24 processes prelamin A, a component of the nuclear lamina; mutations

23 n of a lipid-modified (farnesylated) form of prelamin A, a protein that contributes to the structural

24 eristic of aged VSMCs, and overexpression of prelamin A accelerated VSMC senescence.

25 oes not occur, a farnesylated and methylated prelamin A accumulates in cells, causing a severe proger

26 lamin A missense mutations in the absence of prelamin A accumulation (P = 0.0003 and P < 0.0001).

27 and rats with chronic kidney disease showed prelamin A accumulation and accelerated loss of heteroch

28 Prelamin A accumulation correlated with downregulation o

29 During VSMC aging in vitro, prelamin A accumulation occurred concomitantly with incr

30 In human arteries, prelamin A accumulation was not observed in young health

31 involved in prelamin A processing, leads to prelamin A accumulation, an absence of mature lamin A, m

32 We show that prelamin A acts to disrupt mitosis and induce DNA damage

33 Some data suggest that prelamin A also accumulates with physiological aging.

34 Prelamin A alterations also occur in physiological aging

35 to accumulation of full-length farnesylated prelamin A and cause related progeroid disorders.

36 A FTI also mislocalized prelamin A and improved nuclear shape in Zmpste24-defici

37 e splicing reduces transcripts for wild-type prelamin A and increases transcripts for a truncated pre

38 Thus, at least in the mouse, prelamin A and lamin A appear to be dispensable.

39 s focused on mutations in LMNA (the gene for prelamin A and lamin C) that cause particular muscular d

40 is caused by mutations in LMNA (the gene for prelamin A and lamin C) that result in the deletion of 5

41 ficiency in humans causes an accumulation of prelamin A and leads to lipodystrophy and other disease

42 As expected, non-farnesylated prelamin A and non-farnesylated DNAJA1 accumulated in Fn

43 y of Zmpste24 in mice causes accumulation of prelamin A and phenotypic features similar to MAD.

44 erlying exaggerated CVD and aging induced by prelamin A and progerin.

45 e significantly impaired in VSMCs expressing prelamin A and that chemical inhibition and siRNA deplet

46 AO) that yields exclusively non-farnesylated prelamin A (and no lamin C).

47 ical knock-in allele yielding only wild-type prelamin A appeared normal.

48 use brain, whereas lamin A and its precursor prelamin A are restricted to endothelial cells and menin

49 icate that progerin and full-length farnesyl-prelamin A are toxic to neurons of the enteric nervous s

50 e studies identify ASO-mediated reduction of prelamin A as a potential strategy to treat prelamin A-s

51 Nevertheless, an accumulation of farnesyl-prelamin A (as occurs with a deficiency in the prelamin

52 sor, prelamin A, lead to the accumulation of prelamin A at the nuclear envelope, cause misshapen nucl

53 asonably ascribed to defective processing of prelamin A, but the brittle bone phenotype suggests a br

54 Lamin A is formed from prelamin A by four post-translational processing steps-f

55 ent of the nuclear lamina, is generated from prelamin A by four post-translational processing steps:

56 zed by MS and identified as calreticulin and prelamin A/C.

57 tion of a farnesylated, truncated variant of prelamin A called "progerin." We surveyed the diffusiona

58 ing in expression of a truncated, prenylated prelamin A called progerin.

59 ) is caused by the production of a truncated prelamin A, called progerin, which is farnesylated at it

60 In vitro, aged VSMCs rapidly accumulated prelamin A coincidently with nuclear morphology defects,

61 s migrated more rapidly than nonfarnesylated prelamin A, comigrating with the farnesylated form of pr

62 The farnesylation status of prelamin A determines its ability to bind to Narf.

63 f prelamin A regulation likely explains why "prelamin A diseases" such as Hutchinson-Gilford progeria

64 In progeria, the accumulation of farnesyl-prelamin A disrupts this scaffolding, leading to misshap

65 a model to study the effects of farnesylated prelamin A during physiological aging.

66 This peptide acts as a substrate for the prelamin A endoprotease in vitro, with cleavage of the s

67 In coculture experiments, prelamin A-expressing VSMCs induced alkaline phosphatase

68 The down-regulation of prelamin A expression in the brain could explain why mou

69 n remains unclear, but it is intriguing that prelamin A expression in the brain is low and is regulat

70 ing and assessed the feasibility of reducing prelamin A expression in vivo.

71 are present at high levels in the brain, but prelamin A expression levels are very low-due to regulat

72 human vessels, in a mouse model of inducible prelamin A expression, and in a rat model of chronic kid

73 Further studies showed that prelamin A expression, but not lamin C expression, is do

74 Inhibition of prelamin A farnesylation in buccal mucosa cells of patie

75 essing exclusively progerin (a toxic form of prelamin A found in Hutchinson-Gilford progeria syndrome

76 ited the endoproteolytic processing of a GFP-prelamin A fusion protein.

77 does it lead to an accumulation of farnesyl-prelamin A in cells.

78 The mutant prelamin A in HGPS, which is commonly called progerin, r

79 The prelamin A in HIV-PI-treated fibroblasts migrated more r

80 ified mice that express full-length farnesyl-prelamin A in neurons (Zmpste24-deficient mice carrying

81 The accumulation of farnesyl-prelamin A in response to HIV-PI treatment was exaggerat

82 e proposed that miR-9-mediated regulation of prelamin A in the brain could explain the absence of pri

83 Thus, an accumulation of prelamin A in the setting of HIV-PIs represents a plausi

84 We suspected that the non-farnesylated prelamin A in the tissues of these mice would be strikin

85 of carboxy terminal residues of farnesylated prelamin A in two steps to form mature lamin A.

86 fering RNA knockdown of FACE1 reiterated the prelamin A-induced nuclear morphology defects characteri

87 eletion is predicted to affect processing of prelamin A into lamin A.

88 In normal cells, prelamin A is a "CAAX protein" that is farnesylated and

89 Prelamin A is a farnesylated precursor of lamin A, a nuc

90 This study shows that prelamin A is a novel biomarker of VSMC aging and diseas

91 The prenyl-dependent binding of Narf to prelamin A is an important first step in understanding t

92 uncated mutant protein termed "progerin." WT prelamin A is anchored to the nuclear envelope by a farn

93 Prelamin A is farnesylated and methylated on the cystein

94 We hypothesized that the farnesylation of prelamin A is important for its targeting to the nuclear

95 Evidence suggests prelamin A is imported directly into the nucleus where i

96 In the nucleus, prelamin A is processed to lamin A by endoproteolytic re

97 Prelamin A is subsequently internally cleaved by the zin

98 In both HGPS and RD, the farnesyl-prelamin A is targeted to the nuclear envelope, where it

99 Prelamin A is the only known mammalian substrate for ZMP

100 These data suggest that prelamin A is toxic and that reducing its levels by as l

101 PLA (prelamin A) is a biomarker of vascular smooth muscle cel

102 caused by the production of a mutant form of prelamin A known as progerin.

103 of lamin A from its farnesylated precursor, prelamin A, lead to the accumulation of prelamin A at th

104 A-specific antisense oligonucleotide reduced prelamin A levels and significantly reduced the frequenc

105 As expected, prelamin A levels in Zmpste24(-/-)Lmna(+/-) cells were s

106 in progeria arising from genetic defects in prelamin A maturation.

107 We hypothesized that prelamin A might be toxic and that its accumulation in Z

108 and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant-negativ

109 HGPS), a rare genetic disorder caused by the prelamin A mutant progerin.

110 ) mice were indistinguishable from those in "prelamin A-only" mice (Lmna(PLAO/PLAO)), where all of th

111 Mutations in the genes encoding either prelamin A or ZMPSTE24 that prevent cleavage cause the p

112 caused by the retention of farnesyl lipid on prelamin A, or by the retention of the last 15 amino aci

113 We monitored the proteolysis of farnesylated prelamin A peptide by ZMPSTE24 and unexpectedly found re

114 ibitors and showed that drug binding blocked prelamin A peptide cleavage and conferred stability to Z

115 tory phenotype factors/cytokines released by prelamin A-positive VSMCs, including the calcification r

116 It remains unknown how defective prelamin A processing affects the cardiac rhythm.

117 elamin A (as occurs with a deficiency in the prelamin A processing enzyme Zmpste24) caused dramatical

118 ion mutations in ZMPSTE24, which encodes the prelamin A processing enzyme, lead to accumulation of fu

119 We conclude that prelamin A processing is dispensable in mice and that di

120 Prelamin A processing was defective both in fibroblasts

121 Here we have reexamined the cellular site of prelamin A processing, and show that the mammalian and y

122 s a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterat

123 ficiency in ZMPSTE24, a protease involved in prelamin A processing, leads to prelamin A accumulation,

124 ecause ZMPSTE24 has functions in addition to prelamin A processing, we generated a mouse model to exa

125 tions in ZMPSTE24 may cause MAD by affecting prelamin A processing.

126 ermopathy (RD), is caused by the loss of the prelamin A-processing enzyme, ZMPSTE24.

127 n in LMNA leading to expression of truncated prelamin A (progerin) in the nucleus.

128 HGPS results from a dominant mutant form of prelamin A (progerin) that has an internal deletion of 5

129 of an internally truncated form of farnesyl-prelamin A (progerin).

130 A and increases transcripts for a truncated prelamin A (progerin).

131 ogeria syndrome (HGPS) is caused by a mutant prelamin A, progerin, that terminates with a farnesylcys

132 Prelamin A promotes VSMC calcification and aging by indu

133 ng in production of a truncated farnesylated-prelamin A protein (progerin).

134 duced the expression of progerin, the mutant prelamin A protein in HGPS, in fibroblasts derived from

135 Here, we identify nuclear prelamin A recognition factor (NARF) as a hypoxia-induci

136 -like protein 1 (IOP1; also known as nuclear prelamin A recognition factor like protein, or NARFL) is

137 ein 1 (IOP1) and IOP2 (also known as nuclear prelamin A recognition factor).

138 y hydrogenase-like protein 1)/NARFL (nuclear prelamin A recognition factor-like), a cytosolic protein

139 This form of prelamin A regulation likely explains why "prelamin A di

140 Failure to cleave prelamin A results in progeria and related premature agi

141 mutagenized the eight residues flanking the prelamin A scissile bond (TRSY LLGN) to all other 19 ami

142 Moreover, treating Zmpste24-/- cells with a prelamin A-specific antisense oligonucleotide reduced pr

143 prelamin A as a potential strategy to treat prelamin A-specific diseases.

144 progeria syndrome (HGPS), that are caused by prelamin A-specific mutations could be treated by shifti

145 The apparent dispensability of prelamin A suggested that lamin A-related progeroid synd

146 ynthesize mature lamin A directly, bypassing prelamin A synthesis and processing.

147 s might be treated with impunity by reducing prelamin A synthesis.

148 ation or deletion of the CaaX motif from the prelamin A tail domain inhibits Narf binding in yeast tw

149 A, comigrating with the farnesylated form of prelamin A that accumulates in ZMPSTE24-deficient fibrob

150 ice have an L648R amino acid substitution in prelamin A that blocks ZMPSTE24-catalyzed processing to

151 ogeria syndrome (HGPS) is caused by a mutant prelamin A that cannot be processed to lamin A.

152 disease caused by the synthesis of a mutant prelamin A that cannot undergo processing to lamin A.

153 tion that leads to the synthesis of a mutant prelamin A that is farnesylated but cannot be further pr

154 tively spliced products of LMNA, lamin C and prelamin A (the precursor to lamin A), are produced in s

155 O)), which produce lamin C but no lamin A or prelamin A (the precursor to lamin A).

156 orms a key proteolytic step in maturation of prelamin A, the farnesylated precursor of the nuclear sc

157 Prelamin A, the unprocessed form of the nuclear lamina p

158 e of the presumed lack of ZMPSTE24 activity, prelamin A, the unprocessed toxic form of lamin A, was d

159 lloproteinase required for the processing of prelamin A to lamin A, a structural component of the nuc

160 s the endoproteolytic processing of farnesyl-prelamin A to mature lamin A and leads to the accumulati

161 able in mice and that the failure to convert prelamin A to mature lamin A causes cardiomyopathy (at l

162 ne protease plays a major role in converting prelamin A to mature lamin A.

163 ed 15-amino acid tail from the C-terminus of prelamin A to yield mature lamin A.

164 ents that target the DNA damage response and prelamin A toxicity may be potential therapies for the t

165 Prelamin A transcript levels were low in the brain, but

166 ion levels are very low-due to regulation of prelamin A transcripts by microRNA 9.

167 no lamin A, a consequence of the removal of prelamin A transcripts by miR-9, a brain-specific microR

168 a Lmna knock-in allele yielding full-length prelamin A transcripts lacking a miR-9 binding site).

169 all the output of the gene is channeled into prelamin A transcripts, large amounts of lamin A were fo

170 Accumulation of the farnesylated prelamin A variant progerin, with an internal deletion i

171 Cleavage of prelamin A variants was assessed using an in vivo yeast

172 with a farnesyltransferase inhibitor (FTI), prelamin A was partially mislocalized away from the nucl

173 creased lamin C production at the expense of prelamin A when transfected into mouse and human fibrobl

174 caused by the synthesis of a mutant form of prelamin A, which is generally called progerin.

175 ls of GFP-progerin or an uncleavable form of prelamin A with a Zmpste24 cleavage site mutation induce

176 Lamin A is synthesized as a precursor (prelamin A) with a C-terminal CaaX motif that undergoes

177 is first synthesized as a 74-kDa precursor, prelamin A, with a C-terminal CaaX motif and undergoes a

178 24 deficiency results in the accumulation of prelamin A within cells, a complete loss of mature lamin

179 mpste24(-/-) mice with half-normal levels of prelamin A (Zmpste24(-/-) mice with one Lmna knockout al