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

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

4 ctive processing and nuclear accumulation of prelamin A.

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

6 g mice lacking the farnesylated CAAX protein prelamin A.

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

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

9 ulation of farnesylated, membrane-associated prelamin A.

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

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

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

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

14 biogenesis and leading to an accumulation of prelamin A.

15 the accumulation of the farnesylated form of prelamin A.

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

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

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

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

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

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

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

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

24 Prelamin A accumulation correlated with downregulation o

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

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

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

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

29 Prelamin A alterations also occur in physiological aging

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

81 Prelamin A is farnesylated and methylated on the cystein

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

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

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

85 Prelamin A is subsequently internally cleaved by the zin

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

104 Prelamin A processing was defective both in fibroblasts

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

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

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

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

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

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

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

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

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

114 Prelamin A promotes VSMC calcification and aging by indu

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

154 24 deficiency results in the accumulation of prelamin A within cells, a complete loss of mature lamin

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