Linked Life Data

16707502

Source:http://linkedlifedata.com/resource/pubmed/id/16707502

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
29
pubmed:dateCreated
2006-7-17
pubmed:abstractText
The connective tissue growth factor known as CCN2 is an inducible, profibrotic molecule that becomes aberrantly expressed in mechanical overload-bearing tissues. In this study, we found that CCN2 gene expression is rapidly induced in cyclically stretched bladder smooth muscle cells (SMCs) in vitro and in the detrusor muscle of a mechanically overloaded bladder in a rat model of experimental urethral obstruction. The activity of CCN2 promoter constructs, transiently transfected into cultured SMCs, was increased (up to 6-fold) by continuous cyclic stretching. Molecular analyses of the CCN2 promoter by serial construct deletions, cis-element mutagenesis, and electrophoretic mobility shift assays revealed that a highly conserved NF-kappaB binding site located within the CCN2 proximal promoter region is responsible for the activation of the promoter by stretch. Chromatin immunoprecipitation assays showed that NF-kappaB binds to the endogenous CCN2 promoter in both stretched cells and mechanically overloaded bladder tissues. Furthermore, stretch-dependent CCN2 promoter activity was significantly reduced upon inhibition of either phosphatidylinositol 3-kinase, p38 stress-activated kinase, or RhoA GTPase and was completely abolished upon inhibition of actin polymerization. Concordantly, actin polymerization was increased in either mechanically stretched cells or overloaded bladder tissues. Incubation of cultured SMCs with a cell-penetrating peptide containing the N-terminal sequence, Ac-EEED, of smooth muscle alpha-actin, altered both actin cytoskeleton organization and stretch-mediated nuclear relocation of NF-kappaB, and subsequently, it reduced CCN2 promoter activity. Thus, mechanical stretch-induced changes in actin dynamics mediate NF-kappaB activation and induce CCN2 gene expression, which probably initiates the fibrotic reactions observed in mechanical overload-associated pathologies.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
21
pubmed:volume
281
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
20608-22
pubmed:dateRevised
2011-9-22
pubmed:meshHeading
pubmed-meshheading:16707502-Amino Acid Sequence, pubmed-meshheading:16707502-Animals, pubmed-meshheading:16707502-Base Sequence, pubmed-meshheading:16707502-Connective Tissue Growth Factor, pubmed-meshheading:16707502-DNA Primers, pubmed-meshheading:16707502-Immediate-Early Proteins, pubmed-meshheading:16707502-Intercellular Signaling Peptides and Proteins, pubmed-meshheading:16707502-Molecular Sequence Data, pubmed-meshheading:16707502-Muscle, Smooth, pubmed-meshheading:16707502-Mutagenesis, Site-Directed, pubmed-meshheading:16707502-Mutant Chimeric Proteins, pubmed-meshheading:16707502-NF-kappa B, pubmed-meshheading:16707502-Promoter Regions, Genetic, pubmed-meshheading:16707502-RNA, pubmed-meshheading:16707502-RNA, Messenger, pubmed-meshheading:16707502-Rats, pubmed-meshheading:16707502-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:16707502-Sequence Alignment, pubmed-meshheading:16707502-Sequence Homology, Nucleic Acid, pubmed-meshheading:16707502-Stress, Mechanical, pubmed-meshheading:16707502-Urinary Bladder
pubmed:year
2006
pubmed:articleTitle
Mechanical stretch modulates the promoter activity of the profibrotic factor CCN2 through increased actin polymerization and NF-kappaB activation.
pubmed:affiliation
Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA. bchaqour@downstate.edu
pubmed:publicationType
Journal Article, Comparative Study, Research Support, N.I.H., Extramural