ライフサイエンスコーパス: progerin

1 ases transcripts for a truncated prelamin A (progerin).

2 /+ mice (which produce lamin A, lamin C, and progerin).

3 rboxymethylation of the mutant LA (LADelta50/progerin).

4 nally truncated form of farnesyl-prelamin A (progerin).

5 a truncated farnesylated-prelamin A protein (progerin).

6 GPS fibroblasts, increasing the synthesis of progerin.

7 ogeria caused by the expression of LADelta50/progerin.

8 tion of a mutant form of prelamin A known as progerin.

9 of a truncated, prenylated prelamin A called progerin.

10 trapping of NRF2 at the nuclear periphery by progerin.

11 orm of prelamin A, which is generally called progerin.

12 foci in the primary keratinocytes expressing progerin.

13 roduction of a mutant lamin A protein termed progerin.

14 1) is impaired in cells expressing LADelta50/progerin.

15 as in HGPS cells and in cells expressing GFP-progerin.

16 and/or carboxylmethyl CaaX modifications on progerin.

17 n contrast, this cleavage site is deleted in progerin.

18 A yielding the farnesylated aberrant protein progerin.

19 ng function of LAP2alpha in cells expressing progerin.

20 ulting in a truncated form of lamin A called progerin.

21 ected from functional deleterious effects of progerin.

22 ng toxicity of the disease-producing protein progerin.

23 is sufficient to induce ROS irrespective of progerin.

24 ng disorder caused by a lamin A mutant named progerin.

25 the forks, whereas PCNA efficiently bound to progerin.

26 ssion of a truncated form of Lamin A, called progerin.

27 dominant-negative lamin A protein, known as progerin.

28 s the farnesylated aberrant lamin A protein, progerin.

29 ated CVD and aging induced by prelamin A and progerin.

30 tic disorder caused by the prelamin A mutant progerin.

31 sulting in a mutant lamin A protein known as progerin.

32 so known as PRKDC) as a downstream target of progerin.

33 Also, in knockin mice expressing exclusively progerin (a toxic form of prelamin A found in Hutchinson

34 ease is caused by constitutive production of progerin, a mutant form of the nuclear architectural pro

35 Progerin, a mutated lamin A, causes the severe premature

36 Our approach involves expression of progerin, a truncated form of lamin A associated with pr

37 (LMNA) gene, resulting in the generation of progerin, a truncated splicing mutant of lamin A.

38 we present evidence that the mutant lamin A (progerin) accumulates in the nucleus in a cellular age-d

39 Progerin accumulation has not only been described in HGP

40 Importantly, progerin accumulation stimulates a powerful suppression

41 tures, we observed, concomitantly to nuclear progerin accumulation, severe nuclear envelope deformati

42 Hutchinson-Gilford progeria syndrome (termed progerin) acts as a dominant negative protein that chang

43 The presence of progerin adversely affects the integrity of the nuclear

44 A progerin allele of lamin-A is regulated in the same mann

45 Because progerin also accumulates during physiological ageing, o

46 ading us to hypothesize that nonfarnesylated progerin also might be capable of eliciting disease.

47 g disorder caused by nuclear accumulation of progerin, an altered form of the Lamin A gene.

48 Our findings indicate that progerin and full-length farnesyl-prelamin A are toxic t

49 e nuclear morphology of cells expressing GFP-progerin and in HGPS cells.

50 Upon differentiation of HGPS-iPSCs, progerin and its ageing-associated phenotypic consequenc

51 henotypes of Lmna HG/LCO mice (which produce progerin and lamin C) with littermate Lmna HG/+ mice (wh

52 an influence both the steady-state levels of progerin and the severity of progeria-like disease pheno

53 ng of the C-terminus of the mutant protein, 'progerin', and found that it does not undergo cleavage a

54 HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelop

55 Abnormal lamin A (progerin) appears to accumulate with aging in normal cel

56 ur data suggest that the cellular effects of progerin are transduced, at least in part, through reduc

57 NRF2 activity in HGPS patient cells reverses progerin-associated nuclear aging defects and restores i

58 esyltransferase inhibitors (FTI) mislocalize progerin away from the nuclear envelope and reduce the f

59 e farnesyltransferase inhibitor mislocalized progerin away from the nuclear envelope to the nucleopla

60 her hypothesized that the mislocalization of progerin away from the nuclear envelope would improve th

61 In this study, we determined that progerin binds directly to lamin A/C and induces profoun

62 s pre-lamin A cleavage mimics the effects of progerin by disrupting the Ran gradient, but the effects

63 However, the mechanism how progerin causes disease remains unclear.

64 Progerin causes extensive atherosclerosis and cardiac el

65 iduals, but it is not clear if low levels of progerin contribute to the aging of the brain.

66 Analyses including NLS swapping revealed Progerin did not cause global inhibition of nuclear impo

67 Depletion of XPA or progerin each significantly restored PCNA at replication

68 uggest that this approach may be limited, as progerin elicits disease phenotypes whether or not it is

69 ely satisfying because it is unclear whether progerin-even if were expressed in neurons-would be capa

70 Forcing the nuclear localization of Ubc9 in progerin-expressing cells rescues the Ran gradient and T

71 Similarly, spontaneous immortalization of progerin-expressing cultured keratinocytes selected for

72 This defect in progerin-expressing vascular smooth muscle cells is asso

73 VB) and found that UVA, but not UVB, induces progerin expression and HGPS-like abnormal nuclear shape

74 ced lamin A expression in wild-type mice and progerin expression in an HGPS mouse model.

75 ety of cell-based assays, we determined that progerin expression in Hutchinson-Gilford progeria syndr

76 The cellular consequences of progerin expression underlying the HGPS phenotype remain

77 early proliferative defects associated with progerin expression.

78 syndrome (HGPS) fibroblasts that express the Progerin form of lamin A, causing a major defect in nucl

79 Expression of a GFP-progerin fusion protein in normal fibroblasts caused a h

80 In addition, low levels of progerin have also been found in several tissues from no

81 lted in abnormal nuclear localization of GFP-progerin in comparison with the localization pattern of

82 ions in keratinocyte nuclei, mice expressing progerin in epidermis had normal hair grown and wound he

83 We generated transgenic mice expressing progerin in epidermis under control of a keratin 14 prom

84 We found that expression of progerin in iPSC-derived fibroblasts and neurons induces

85 ese differences was uncovered; the amount of progerin in Lmna HG/LCO fibroblasts and tissues was lowe

86 The steady-state levels of progerin in LmnanHG/+ MEFs and tissues were lower, sugge

87 ice harboring the Lmna(HG-C) allele produced progerin in neurons, but they had no pathology in the ce

88 on-Gilford progeria syndrome), the levels of progerin in the brain were extremely low.

89 ults implicate the abnormal farnesylation of progerin in the cellular phenotype in HGPS cells and sug

90 lts support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3

91 Accumulation of progerin in the nuclei of HGPS cells impairs nuclear fun

92 Also, blocking farnesylation of authentic progerin in transiently transfected HeLa, HEK 293, and N

93 The synthesis of progerin in wild-type fibroblasts was accompanied by the

94 stably expressed lamin A mutants, including progerin, in otherwise identical primary human fibroblas

95 Thus, our study suggests that progerin-induced aging can be used to reveal late-onset

96 Furthermore, we demonstrated that progerin-induced apoptosis could be rescued by XPA, sugg

97 e3, whereas lowering LAP2 levels exacerbates progerin-induced defects.

98 iously reported that XPA mislocalized to the progerin-induced DNA double-strand break (DSB) sites, bl

99 Our results propose a mechanism for progerin-induced genome instability and accelerated repl

100 PS since increasing LAP2alpha levels rescues progerin-induced proliferation defects and loss of H3K27

101 Although progerin induces significant alterations in keratinocyte

102 ernative splicing of the LMNA transcript, as progerin induction was suppressed by the singlet oxygen

103 Rather, Progerin inhibited Tpr import because transport of large

104 isplay elevated ROS, these data suggest that progerin inhibits nuclear transport via oxidative stress

105 Progerin is a mutant form of lamin A responsible for Hut

106 Recent studies have demonstrated that progerin is also produced at low levels in normal human

107 This finding suggests that accumulation of progerin is directly involved in vascular disease in pro

108 The induction of progerin is mediated by UVA-induced oxidative damage and

109 cts with lamin A, while its interaction with progerin is significantly reduced.

110 Progerin is targeted to the nuclear envelope and causes

111 Progerin is targeted to the nuclear rim, where it interf

112 Accumulation of progerin is thought to underlie the pathophysiology of H

113 During interphase, irreversibly farnesylated progerin/LADelta50 anchors to the nuclear membrane and c

114 ng normal cells are binucleated, implicating progerin/LADelta50 as causing similar mitotic defects in

115 ermore, we demonstrate that small amounts of progerin/LADelta50 exist in normal fibroblasts, and a si

116 Here, we report that progerin/LADelta50 mislocalizes into insoluble cytoplasm

117 ing in a mutant lamin A (LA) protein termed "progerin/LADelta50" that lacks the normal cleavage site

118 Progerin/LADelta50's localization and behavior during mi

119 lasts, and a significant percentage of these progerin/LADelta50-expressing normal cells are binucleat

120 bitors or a farnesylation-incompetent mutant progerin/LADelta50.

121 itors with the ability to block pathological progerin-lamin A/C binding may represent a promising str

122 (JH1, JH4, and JH13) that efficiently block progerin-lamin A/C binding.

123 Expression of progerin leads to alterations in nuclear morphology, whi

124 We find that expression of progerin leads to inhibition of proliferation in a high

125 However, the mechanisms of how progerin leads to massive SMC loss are unknown.

126 Accumulation of progerin leads to various ageing-associated nuclear defe

127 roblasts transfected with these ASOs exhibit progerin levels similar to (or greater than) those in fi

128 splicing in HGPS cells and modestly lowered progerin levels.

129 a gene-targeted allele yielding exclusively progerin (Lmna HG) and found that heterozygous mice (Lmn

130 nd knock-in allele yielding non-farnesylated progerin (Lmna(csmHG)) in which the carboxyl-terminal -C

131 showed that mice expressing non-farnesylated progerin (Lmna(nHG/+) mice, in which progerin's carboxyl

132 ated knockin mice expressing nonfarnesylated progerin (LmnanHG/+).

133 These findings lead us to propose that progerin may interfere with telomere structure or metabo

134 We speculate that oxidative stress caused by progerin may occur upstream or downstream of Ran, depend

135 ence, providing mechanistic insight into how progerin may participate in the normal aging process.

136 ing replication forks, PCNA sequestration by progerin may shift the equilibrium to favor XPA binding.

137 ed to oxidative stress resist the effects of progerin on Ran and Ubc9.

138 we find that expression in HeLa cells of GFP-progerin or an uncleavable form of prelamin A with a Zmp

139 r improve disease by additionally inhibiting progerin prenylation.

140 elationship between telomere dysfunction and progerin production during the induction of cell senesce

141 effect relationship between normal aging and progerin production in normal individuals has not yet be

142 Interestingly, elevated progerin production was not seen during cellular senesce

143 escence plays a causative role in activating progerin production.

144 cular calcification in normal aging, because progerin progressively accumulates in the vascular tissu

145 We found that progerin reduces the nuclear/cytoplasmic concentration o

146 SSIM progerin relocalized from the nuclear periphery into nuc

147 expression of LAP2alpha in cells expressing progerin restores proliferation and extracellular matrix

148 Progerin retains a farnesyl lipid anchor at its carboxyl

149 prelamin A in HGPS, which is commonly called progerin, retains the CAAX motif that triggers farnesyla

150 sylated progerin (Lmna(nHG/+) mice, in which progerin's carboxyl-terminal -CSIM motif was changed to

151 transferase inhibitor (FTI), suggesting that progerin's farnesyl lipid is important for disease patho

152 Progerin sequesters NRF2 and thereby causes its subnucle

153 Progerin sequestration of PCNA promotes replication fork

154 Without progerin-specific treatment, death occurs at an average

155 s from a dominant mutant form of prelamin A (progerin) that has an internal deletion of 50 aa near th

156 ome (HGPS) is caused by a mutant prelamin A, progerin, that terminates with a farnesylcysteine.

157 Association of progerin, the lamin A isoform responsible for the premat

158 The same ASO also reduced the expression of progerin, the mutant prelamin A protein in HGPS, in fibr

159 Here we explore the relationship between progerin, the Ran GTPase, and oxidative stress.

160 that retention of the farnesyl group causes progerin to become permanently anchored in the nuclear m

161 es show that the ability of non-farnesylated progerin to elicit disease depends on the carboxyl-termi

162 n farnesylation would block the targeting of progerin to the nuclear envelope, and we further hypothe

163 Stable attachment of progerin to the nuclear membrane disrupts the Ran gradie

164 tachment of a mutant form of lamin A (termed progerin) to the nuclear membrane.

165 d that blocking farnesylation would decrease progerin toxicity.

166 knock-in allele, Lmna(HG-C), which produces progerin transcripts lacking an miR-9 binding site.

167 Progerin triggers loss of the heterochromatic marker H3K

168 This progerin was farnesylated, as judged by metabolic labeli

169 is hypothesis, the terminal CSIM sequence in progerin was mutated to SSIM, a sequence that cannot be

170 alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells.

171 production of a truncated prelamin A, called progerin, which is farnesylated at its carboxyl terminus

172 e and knock-in Lmna(G609G/+) mice expressing progerin, which mimic the main clinical manifestations o

173 This mutation generates the lamin A variant progerin, which we show here leads to loss of LAP2alpha

174 t produces a mutant lamin A protein, termed "progerin," which carries a 50-aa deletion near its C ter

175 We hypothesized that accumulation of progerin with abnormal nuclear shapes may also be accele

176 s cause an abnormal association of LADelta50/progerin with membranes during mitosis, which delays the

177 d LMNA mutation results in a protein, termed progerin, with an internal 50 amino acid deletion and, u

178 producing a truncated mutant protein termed "progerin." WT prelamin A is anchored to the nuclear enve