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Effect of progerin on p53-deficient vascular smooth muscle cells

ABSTRACT: Analysis of p53-deficient (E6-expressing) human vascular smooth muscle cells (VSMCs) that express progerin, a mutated form of lamin A resposible for Hutchinson- Gilford progeria syndrome (HGPS). p53 pathway is associated with HGPS. Results provide insight into molecular mechanisms underlying vascular dysfunction of HGPS caused by other than p53 pathway. The gene expression of VSMCs induced to express E6 and either lamin A or progerin by retroviral vectors.

ORGANISM(S): Homo sapiens

SUBMITTER: Daisuke Kinoshita

PROVIDER: E-GEOD-47553 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Effect of progerin on p53-deficient vascular smooth muscle cells

Project description:Analysis of p53-deficient (E6-expressing) human vascular smooth muscle cells (VSMCs) that express progerin, a mutated form of lamin A resposible for Hutchinson- Gilford progeria syndrome (HGPS). p53 pathway is associated with HGPS. Results provide insight into molecular mechanisms underlying vascular dysfunction of HGPS caused by other than p53 pathway.

2013-09-22 | GSE47553 | GEO

Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant negative lamin A protein, known as progerin. Here we show that HGPS cells experience genome-wide alterations in patterns of H3K27me3 deposition, changes in the associations of genomic loci with nuclear lamin A/C, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains that characterizes chromosome folding in normal cells. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin-lamina interactions. These changes may then lead to the genomic disorganization and changes in transcriptional regulation we observe in HGPS fibroblasts. ChIP-Seq was performed for H3K27me3 and lamin A/C in the human genome in three primary fibroblast cell lines: an HGPS patient (HGPS), normal cells from the father of the HGPS patient (Father), and age-matched normal cells (Age Control). Two biological replicates were performed.

2012-10-30 | E-GEOD-41757 | biostudies-arrayexpress

Progerin-induced changes in gene expression

Project description:The premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A1. Progerin is also sporadically expressed in wild type cells and has been linked to physiological aging. HGPS cells exhibit extensive nuclear defects including abnormal chromatin structure and increased DNA damage. At the organismal level, HGPS affects several tissues particularly of mesenchymal origin. How the cellular defects of HGPS cells lead to the organismal defects has been unclear. To begin to unravel how progerin leads to disease phenotypes, we analyzed time-dependent changes in transcriptional profiles in response to progerin expression in a hTERT-immortalized skin fibroblast cell line expressing either GFP-progerin or the GFP-wt lamin A control Keywords: time course, cell line comparison

2008-02-09 | GSE10123 | GEO

Expression data from mouse perigonadal white adipose tissue - various mutant conditions [gene-level analysis]

2015-06-05 | GSE51202 | GEO

Expression data from mouse perigonadal white adipose tissue - various mutant conditions [exon-level analysis]

2015-06-05 | GSE51203 | GEO

Expression data from mouse perigonadal white adipose tissue - various mutant conditions [exon-level analysis]

Project description:Progerin-expressing mice (HGPS-like) demonstrated increased energy metabolism and lipodystrophy. Increased mitochondrial biogenesis was found in adipose tissue from HGPS-like mice, whereas lamin C-only mice had fewer mitochondria. Thus we analyse which molecular pathways mediated the changes in adipose tissue caused by lamin C and progerin expression and the roles of these pathways in energy metabolism and aging. 10 cDNAs samples were analysed. We compared the mean fold change of 2 to 4 biological replicates. We performed an unpaired Student’s t-test to compare intensities in the different biological replicates. Genes were considered significantly regulated when the fold change was ? 1.5, and the p-value was ?0.05.

2015-06-05 | E-GEOD-51203 | biostudies-arrayexpress

Expression data from mouse perigonadal white adipose tissue - various mutant conditions [gene-level analysis]

2015-06-05 | E-GEOD-51202 | biostudies-arrayexpress

A human iPSC model of Hutchinson Gilford Progeria Syndrome reveals a possible mesenchymal stem cell defect

Project description:Hutchinson Gilford Progeria Syndrome (HGPS) is a rare, sporadic genetic disease caused by mutations in the nuclear lamin A gene. In most cases the mutation creates an efficient donor-splice site that generates an altered transcript encoding a truncated lamin A protein, progerin. In vitro studies have indicated that progerin can disrupt nuclear function. HGPS affects mainly mesenchymal lineages but the shortage of patient material has precluded a tissue-wide molecular survey of progerin’s cellular impact. We report here a new, induced pluripotent stem cell (iPSC)-based model for studying HGPS. HGPS dermal fibroblasts were reprogrammed into iPSC lines using a cocktail of the transcription factor genes, OCT4, SOX2, KLF4 and C-MYC. The iPSC cells were differentiated into neural progenitors (NPs), endothelial cells (ECs), fibroblast-like cells and mesenchymal stem cells (MSCs). Progerin levels in the different cell types followed the pattern MSC≥ fibroblast>EC>>NP. Functionally, we detected a major impact of progerin on MSC function. We show that HGPS-MSCs are vulnerable to the ischemic conditions found in a murine hind limb recovery model and an in vitro hypoxia assay, as well as showing enhanced sensitivity in a serum starvation assay. Since there is widespread consensus that MSCs reside in low oxygen niches in vivo, we propose that these conditions lead to an accelerated depletion of the MSC pool in HGPS patients with consequent accretion of mesenchymal tissue. Analysis of iPSCs, hESCs and parental fibroblasts at the gene expression level. The comparison analysis in the present study was expected to show the similarity between iPSCs, hESCs and parental fibroblasts. Results provide important information of the differences between iPSCs, hESCs and parental fibroblasts. Total RNA was obtained from different samples (iPSCs, hESCs, and fibroblasts) separately.

2010-12-23 | E-GEOD-26093 | biostudies-arrayexpress

6-Shogaol Inhibits Oxidative Stress-induced Rat Vascular Smooth Muscle Cell Apoptosis by Regulating OXR1-p53 axis

Project description:Apoptosis of vascular smooth muscle cells (VSMCs) is closely related to the pathogenesis of cardiovascular disease, and oxidative stress is an important cause for VSMCs death. Inhibiting VSMCs apoptosis is an effective preventive strategy in slowing down the development of cardiovascular disease, especially for atherosclerosis. In this study, we found OXR1 (oxidation resistance protein 1), a crucial participator for responding for oxidative stress, could modulate the expression of p53, a key regulator of apoptosis. Our results revealed that oxidative stress promoted VSMCs apoptosis by overexpression of OXR1-p53 axis, and 6-shogaol (6S), a major biologically active compound present in ginger, could effectively attenuate cell death by preventing the up-regulated expression of OXR1-p53 axis. Quantitative proteomics analysis revealed that the degradation of p53 mediated by OXR1 might related with the enhanced assembly of SCF ubiquitin ligase complexes, which is reported to closely relate with the modification of ubiquitination or neddylation, and subsequent degradation of p53.

2022-02-22 | PXD015127 | Pride

Quantification of mature lamin A and progerin in HGPS patient cells

Project description:The ratio of progerin to mature lamin A correlates with disease severity in HGPS patients, and can be used to assess the effectiveness of therapies aimed at lessening aberrant splicing and/or progerin farnesylation. We have developed the first non-immunological method, based on a targeted MS approach and the use of isotope-labelled internal standards, that reliably quantifies the levels of wild-type lamin A and farnesylated progerin in cells from HGPS patients.

2023-08-26 | PXD036318 | JPOST Repository

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