Linked Life Data

18363837

Source:http://linkedlifedata.com/resource/pubmed/id/18363837

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2008-9-10
pubmed:abstractText
The patients with Crohn's disease (CD) have a 'leaky gut' manifested by an increase in intestinal epithelial tight junction (TJ) permeability. Tumour necrosis factor-alpha (TNF-alpha) is a proto-typical pro-inflammatory cytokine that plays a central role in intestinal inflammation of CD. An important pro-inflammatory action of TNF-alpha is to cause a functional opening of intestinal TJ barrier. Previous studies have shown that TNF-alpha increase in TJ permeability was regulated by an increase in myosin light chain kinase (MLCK) gene activity and protein expression. The major aim of this study was to elucidate the cellular and molecular mechanisms that mediate basal and TNF-alpha-induced increase in MLCK gene activity. By progressive 5' deletion, minimal MLCK promoter was localized between -313 to +118 on MLCK promoter. A p53 binding site located within minimal promoter region was identified as an essential determinant for basal promoter activity. A 4 bp start site and a 5 bp downstream promoter element were required for MLCK gene activity. TNF-alpha-induced increase in MLCK promoter activity was mediated by NF-kappaB activation. There were eight kappaB binding sites on MLCK promoter. The NF-kappaB1 site at +48 to +57 mediated TNF-alpha-induced increase in MLCK promoter activity. The NF-kappaB2 site at -325 to -316 had a repressive role on promoter activity. The opposite effects on promoter activity were due to differences in the NF-kappaB dimer type binding to the kappaB sites. p50/p65 dimer preferentially binds to the NF-kappaB1 site and up-regulates promoter activity; while p50/p50 dimer preferentially binds to the NF-kappaB2 site and down-regulates promoter activity. In conclusion, we have identified the minimal MLCK promoter region, essential molecular determinants and molecular mechanisms that mediate basal and TNF-alpha-induced modulation of MLCK promoter activity in Caco-2 intestinal epithelial cells. These studies provide novel insight into the cellular and molecular mechanisms that regulate basal and TNF-alpha-induced modulation of MLCK gene activity.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1582-1838
pubmed:author
pubmed:issnType
Print
pubmed:volume
12
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1331-46
pubmed:dateRevised
2010-4-29
pubmed:meshHeading
pubmed-meshheading:18363837-Base Sequence, pubmed-meshheading:18363837-Binding Sites, pubmed-meshheading:18363837-Caco-2 Cells, pubmed-meshheading:18363837-Dimerization, pubmed-meshheading:18363837-Enterocytes, pubmed-meshheading:18363837-Gene Expression Regulation, Enzymologic, pubmed-meshheading:18363837-Genome, Human, pubmed-meshheading:18363837-Humans, pubmed-meshheading:18363837-Molecular Sequence Data, pubmed-meshheading:18363837-Mutation, pubmed-meshheading:18363837-Myosin-Light-Chain Kinase, pubmed-meshheading:18363837-Promoter Regions, Genetic, pubmed-meshheading:18363837-RNA, Small Interfering, pubmed-meshheading:18363837-Transcription Factor RelA, pubmed-meshheading:18363837-Transcription Initiation Site, pubmed-meshheading:18363837-Transfection, pubmed-meshheading:18363837-Tumor Necrosis Factor-alpha, pubmed-meshheading:18363837-Tumor Suppressor Protein p53
pubmed:year
2008
pubmed:articleTitle
Cellular and molecular mechanisms that mediate basal and tumour necrosis factor-alpha-induced regulation of myosin light chain kinase gene activity.
pubmed:affiliation
Department of Internal Medicine, University of New Mexico School of Medicine and Albuquerque Veterans Affairs Medical Center, Albuquerque, NM 87131-0001, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural