Effect of progerin on p53-deficient vascular smooth muscle cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE47553 | GEO | 2013/09/22
SECONDARY ACCESSION(S): PRJNA206061
REPOSITORIES: GEO
Similar Datasets
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. The gene expression of VSMCs induced to express E6 and either lamin A or progerin by retroviral vectors.
2013-09-22 | E-GEOD-47553 | biostudies-arrayexpress
Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, genetic premature aging disorder associated with severe atherosclerosis, often resulting in fatal heart attacks and strokes. Progerin, the mutant protein in HGPS, also is expressed in healthy individuals and may play a role in the development of atherosclerosis during physiologic aging. Here, we provide evidence for a primary involvement of vascular endothelium in the pathogenesis of accelerated atherosclerosis in HGPS. Expression of progerin in cultured human endothelial cells induces a dysfunctional phenotype, manifested by activation of multiple pro-inflammatory, pro-atherogenic genes. In particular, our data implicate endothelial-derived interleukin-1 (IL-1) as a key mediator of a pro-inflammatory vascular phenotype. Endothelial activation also is detectable in a mouse model of HGPS, and appears to be conveyed to neighboring vascular cells via autocrine and paracrine signaling. These new mechanistic insights into the vascular pathobiology of HGPS may have therapeutic implications for this disease. Genome-wide transcriptional profiling was carried out to assess functional phenotypic changes in endothelial cells (EC) as a result of progerin expression. Cultured EC were infected with an adenovirus expressing progerin (Ad-Progerin), and as a control, an adenovirus that did not express any construct (Ad-Null). Experiments were preformed with three different EC cultures.
2010-12-02 | E-GEOD-19270 | biostudies-arrayexpress
Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, genetic premature aging disorder associated with severe atherosclerosis, often resulting in fatal heart attacks and strokes. Progerin, the mutant protein in HGPS, also is expressed in healthy individuals and may play a role in the development of atherosclerosis during physiologic aging. Here, we provide evidence for a primary involvement of vascular endothelium in the pathogenesis of accelerated atherosclerosis in HGPS. Expression of progerin in cultured human endothelial cells induces a dysfunctional phenotype, manifested by activation of multiple pro-inflammatory, pro-atherogenic genes. In particular, our data implicate endothelial-derived interleukin-1 (IL-1) as a key mediator of a pro-inflammatory vascular phenotype. Endothelial activation also is detectable in a mouse model of HGPS, and appears to be conveyed to neighboring vascular cells via autocrine and paracrine signaling. These new mechanistic insights into the vascular pathobiology of HGPS may have therapeutic implications for this disease.
2010-12-02 | GSE19270 | GEO
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
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal human premature aging disease1-5, characterized by premature atherosclerosis and degeneration of vascular smooth muscle cells (SMCs)6-8. HGPS is caused by a single-point mutation in the LMNA gene, resulting in the generation of progerin, a truncated mutant of lamin A. Accumulation of progerin leads to various aging-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin9-12. Here, we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature aging. Upon differentiation of HGPS-iPSCs, progerin and its associated aging consequences are restored. In particular, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescent SMC phenotypes associated with vascular aging. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs) as a component of the progerin-containing protein complex. The absence of nuclear DNAPKcs correlates with premature as well as physiological aging. Since progerin also accumulates during physiological aging6,12,13, our results provide an in vitro iPSC-based model with an acceleration progerin accumulation to study the pathogenesis of human premature and physiological vascular aging. Microarray gene expression profiling was done to: (1) Compare differences between WT fibroblasts and fibroblasts from patients suffering of the Hutchinson-Gilford progeria syndrome (2) Check that iPSC originating from WT and patients are in fact similar to ESC
2011-03-14 | E-GEOD-24487 | biostudies-arrayexpress
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease caused by progerin accumulation. However, the mechanism of how progerin causes cell defects is unclear in HGPS cells. To further investigate the possible mechanism, we used Flag-tagged progerin as bait in mass spectrometry to survey the possible regulatory factors.
2023-01-30 | PXD039136 | Pride
Project description:To model Hutchinson-Gilford Progeria syndrome (HGPS), we differentiated patient-derived induced pluripotent stem cells (iPSCs) to vascular smooth muscle cells (VSMCs). We then performed gene expression profiling analysis using data obtained from RNA-seq of the serially passaged cells at passage7 and passage 14.
2024-03-07 | GSE231761 | GEO
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is the result of a defective form of the lamin A protein called progerin. While progerin is known to disrupt the properties of the nuclear lamina, the underlying mechanisms responsible for the pathophysiology of HGPS remain less clear. Previous studies in our laboratory have shown that progerin expression in murine epidermal basal cells results in impaired stratification and halted development of the skin. Stratification and differentiation of the epidermis is regulated by asymmetric stem cell division. In this dataset, we include the expression data using Affymetrix array. The samples were obtained from basal and suprabasal keratinocyes from 4-day old wild-type and bitransgenic (BT) mice.
2019-08-13 | GSE131310 | GEO
Project description:Hutchinson Gilford Progeria Syndrome is a premature aging disease caused by LMNA gene mutation and the production of a truncated lamin A protein “progerin” that elicits cellular and organismal toxicity. Progerin accumulates in the vasculature, being especially toxic for vascular smooth muscle cells (VSMC). Patients' autopsies show that vessel stiffening, and aortic atherosclerosis is accompanied by VSMC depletion in the medial layer, altered extracellular matrix (ECM), and thickening of the adventitial layer. Mechanisms whereby progerin causes massive VSMC loss and vessel alterations remain poorly understood. Mature VSMC retain phenotypic plasticity and can switch to a synthetic/proliferative phenotype. Here we show that progerin expression in human and mouse VSMC causes a switch towards the synthetic/proliferative phenotype. This switch elicits some level of replication stress in normal cells, which is exacerbated in the presence of progerin, leading to telomere fragility, genomic instability, and ultimately VSMC death. Importantly, calcitriol prevents replication stress, telomere fragility, and genomic instability, reducing VSMC death. In addition, RNAseq analysis shows induction of a profibrotic and proinflammatory aging-associated secretory phenotype upon progerin expression in human primary VSMC. Our data suggest that phenotypic switch-induced replication stress might be an underlying cause of VSMC loss in progeria, which together with loss of contractile features and gain of profibrotic and proinflammatory signatures contribute to vascular stiffness in HGPS. Preventing the phenotypic switch-induced replication stress with compounds such as calcitriol might ameliorate CVD in HGPS patients
2022-03-23 | GSE198983 | GEO
Project description:Disassembly of the nuclear envelope is an essential feature of mammalian cell division controlled by the phosphoryaltion of lamins via cyclin dependent kinases. This process is affected in cells expressing progerin, a lamin A allele found in patients with Hutchinson-Gilford Progeria syndrome. Progerin can inhibit cell proliferation of both normal and tumor cells and this property is largely magnified if its phosphorylation at serine 22 is inhibited by a genetic mutation to generate S22A-progerin. Surprisingly, S22A-progerin acquires the ability to trigger cellular senescence in tumor cells with mutations in the p53 and RB tumor suppression pathways suggesting a novel pathway to control the growth of malignant tumors. We used microarrays to characterize the gene expression changes induced by the S22A-progerin in comparison with the wt-progerin in U-2 OS cell line. U-2 OS cells were infected with a retroviral vector that express S22A-progerin or wt-progerin. After 4 days of infection, RNA was extracted from three independents replicas of each condition. Total RNA was send to Genome Quebec service for hybridization with Affymetrix microarrays.
2014-03-01 | E-GEOD-51349 | biostudies-arrayexpress