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The VCAM-1 gene that encodes the vascular cell adhesion molecule is a target of the Sry-related high mobility group box gene, Sox18.

Identifieur interne : 008707 ( Main/Exploration ); précédent : 008706; suivant : 008708

The VCAM-1 gene that encodes the vascular cell adhesion molecule is a target of the Sry-related high mobility group box gene, Sox18.

Auteurs : Brett M. Hosking [Australie] ; S-C Mary Wang ; Meredith Downes ; Peter Koopman ; George E O. Muscat

Source :

RBID : pubmed:14634005

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English descriptors

Abstract

VCAM-1 (vascular cell adhesion molecule-1) and Sox18 are involved in vascular development. VCAM-1 is an important adhesion molecule that is expressed on endothelial cells and has a critical role in endothelial activation, inflammation, lymphatic pathophysiology, and atherogenesis. The Sry-related high mobility group box factor Sox18 has previously been implicated in endothelial pathologies. Mutations in human and mouse Sox18 leads to hypotrichosis and lymphedema. Furthermore, both Sox18 and VCAM-1 have very similar spatio-temporal patterns of expression, which is suggestive of cross-talk. We use biochemical techniques, cell culture systems, and the ragged opossum (RaOP) mouse model with a naturally occurring mutation in Sox18 to demonstrate that VCAM-1 is an important target of Sox18. Transfection, site-specific mutagenesis, and gel shift analyses demonstrated that Sox18 directly targeted and trans-activated VCAM-1 expression. Importantly, the naturally occurring Sox18 mutant attenuates the expression and activation of VCAM-1 in vitro. Furthermore, in vivo quantitation of VCAM-1 mRNA levels in wild type and RaOP mice demonstrates that RaOP animals show a dramatic and significant reduction in VCAM-1 mRNA expression in lung, skin, and skeletal muscle. Our observation that the VCAM-1 gene is an important target of SOX18 provides the first molecular insights into the vascular abnormalities in the mouse mutant ragged and the human hypotrichosis-lymphedema-telangiectasia disorder.

DOI: 10.1074/jbc.M308512200
PubMed: 14634005


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Le document en format XML

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<term>Cell Adhesion</term>
<term>Cell Culture Techniques</term>
<term>Cell Line</term>
<term>DNA, Complementary (metabolism)</term>
<term>Dose-Response Relationship, Drug</term>
<term>Fibroblasts (metabolism)</term>
<term>Gene Deletion</term>
<term>Glutathione Transferase (metabolism)</term>
<term>High Mobility Group Proteins (genetics)</term>
<term>High Mobility Group Proteins (physiology)</term>
<term>Humans</term>
<term>Luciferases (metabolism)</term>
<term>Male</term>
<term>Mice</term>
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<term>Mutation</term>
<term>Opossums</term>
<term>Plasmids (metabolism)</term>
<term>Promoter Regions, Genetic</term>
<term>RNA, Messenger (metabolism)</term>
<term>Recombinant Fusion Proteins (metabolism)</term>
<term>Reverse Transcriptase Polymerase Chain Reaction</term>
<term>SOXF Transcription Factors</term>
<term>Time Factors</term>
<term>Tissue Distribution</term>
<term>Transcription Factors (genetics)</term>
<term>Transcription Factors (physiology)</term>
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<term>Transcriptional Activation</term>
<term>Transfection</term>
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<term>Allèles</term>
<term>Animaux</term>
<term>Cellules COS</term>
<term>Délétion de gène</term>
<term>Facteurs de transcription (génétique)</term>
<term>Facteurs de transcription (physiologie)</term>
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<term>Facteurs temps</term>
<term>Fibroblastes (métabolisme)</term>
<term>Glutathione transferase (métabolisme)</term>
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<term>Lignée cellulaire</term>
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<term>Mutagenèse dirigée</term>
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<term>Opossum</term>
<term>Plasmides (métabolisme)</term>
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<term>Protéines HMG (physiologie)</term>
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<term>Relation dose-effet des médicaments</term>
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<term>Répartition dans les tissus</term>
<term>Sites de fixation</term>
<term>Souris</term>
<term>Souris de lignée C57BL</term>
<term>Techniques de culture cellulaire</term>
<term>Transcription génétique</term>
<term>Transfection</term>
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<term>Glutathione Transferase</term>
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<term>Plasmids</term>
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<term>ADN complémentaire</term>
<term>ARN messager</term>
<term>Fibroblastes</term>
<term>Glutathione transferase</term>
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<term>Plasmides</term>
<term>Protéines de fusion recombinantes</term>
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<term>Binding Sites</term>
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<term>Cell Adhesion</term>
<term>Cell Culture Techniques</term>
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<term>Dose-Response Relationship, Drug</term>
<term>Gene Deletion</term>
<term>Humans</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Mutagenesis, Site-Directed</term>
<term>Mutation</term>
<term>Opossums</term>
<term>Promoter Regions, Genetic</term>
<term>Reverse Transcriptase Polymerase Chain Reaction</term>
<term>SOXF Transcription Factors</term>
<term>Time Factors</term>
<term>Tissue Distribution</term>
<term>Transcription, Genetic</term>
<term>Transcriptional Activation</term>
<term>Transfection</term>
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<term>Sites de fixation</term>
<term>Souris</term>
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<front>
<div type="abstract" xml:lang="en">VCAM-1 (vascular cell adhesion molecule-1) and Sox18 are involved in vascular development. VCAM-1 is an important adhesion molecule that is expressed on endothelial cells and has a critical role in endothelial activation, inflammation, lymphatic pathophysiology, and atherogenesis. The Sry-related high mobility group box factor Sox18 has previously been implicated in endothelial pathologies. Mutations in human and mouse Sox18 leads to hypotrichosis and lymphedema. Furthermore, both Sox18 and VCAM-1 have very similar spatio-temporal patterns of expression, which is suggestive of cross-talk. We use biochemical techniques, cell culture systems, and the ragged opossum (RaOP) mouse model with a naturally occurring mutation in Sox18 to demonstrate that VCAM-1 is an important target of Sox18. Transfection, site-specific mutagenesis, and gel shift analyses demonstrated that Sox18 directly targeted and trans-activated VCAM-1 expression. Importantly, the naturally occurring Sox18 mutant attenuates the expression and activation of VCAM-1 in vitro. Furthermore, in vivo quantitation of VCAM-1 mRNA levels in wild type and RaOP mice demonstrates that RaOP animals show a dramatic and significant reduction in VCAM-1 mRNA expression in lung, skin, and skeletal muscle. Our observation that the VCAM-1 gene is an important target of SOX18 provides the first molecular insights into the vascular abnormalities in the mouse mutant ragged and the human hypotrichosis-lymphedema-telangiectasia disorder.</div>
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