Linked Life Data

12904305

Source:http://linkedlifedata.com/resource/pubmed/id/12904305

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
41
pubmed:dateCreated
2003-10-6
pubmed:abstractText
Tissue inhibitor of metalloproteinase (TIMP-1) is a natural protease inhibitor of matrix metalloproteinases (MMPs). Recent studies revealed a novel function of TIMP-1 as a potent inhibitor of apoptosis in mammalian cells. However, the mechanisms by which TIMP-1 exerts its anti-apoptotic effect are not understood. Here we show that TIMP-1 activates cell survival signaling pathways involving focal adhesion kinase, phosphatidylinositol 3-kinase, and ERKs in human breast epithelial cells to TIMP-1. TIMP-1-activated cell survival signaling down-regulates caspase-mediated classical apoptotic pathways induced by a variety of stimuli including anoikis, staurosporine exposure, and growth factor withdrawal. Consistently, down-regulation of TIMP-1 expression greatly enhances apoptotic cell death. In a previous study, substitution of the second amino acid residue threonine for glycine in TIMP-1, which confers selective MMP inhibition, was shown to obliterate its anti-apoptotic activity in activated hepatic stellate cells suggesting that the anti-apoptotic activity of TIMP-1 is dependent on MMP inhibition. Here we show that the same mutant inhibits apoptosis of human breast epithelial cells, suggesting different mechanisms of TIMP-1 regulation of apoptosis depending on cell types. Neither TIMP-2 nor a synthetic MMP inhibitor protects breast epithelial cells from intrinsic apoptotic cell death. Furthermore, TIMP-1 enhances cell survival in the presence of the synthetic MMP inhibitor. Taken together, the present study unveils some of the mechanisms mediating the anti-apoptotic effects of TIMP-1 in human breast epithelial cells through TIMP-1-specific signal transduction pathways.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
10
pubmed:volume
278
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
40364-72
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:12904305-Apoptosis, pubmed-meshheading:12904305-Base Sequence, pubmed-meshheading:12904305-Breast, pubmed-meshheading:12904305-Cell Survival, pubmed-meshheading:12904305-DNA, Complementary, pubmed-meshheading:12904305-Down-Regulation, pubmed-meshheading:12904305-Enzyme Activation, pubmed-meshheading:12904305-Epithelial Cells, pubmed-meshheading:12904305-Female, pubmed-meshheading:12904305-Focal Adhesion Kinase 1, pubmed-meshheading:12904305-Focal Adhesion Protein-Tyrosine Kinases, pubmed-meshheading:12904305-Humans, pubmed-meshheading:12904305-MAP Kinase Signaling System, pubmed-meshheading:12904305-Matrix Metalloproteinases, pubmed-meshheading:12904305-Phosphatidylinositol 3-Kinases, pubmed-meshheading:12904305-Protein-Tyrosine Kinases, pubmed-meshheading:12904305-Tissue Inhibitor of Metalloproteinase-1, pubmed-meshheading:12904305-Transfection
pubmed:year
2003
pubmed:articleTitle
Tissue inhibitor of metalloproteinase-1 protects human breast epithelial cells against intrinsic apoptotic cell death via the focal adhesion kinase/phosphatidylinositol 3-kinase and MAPK signaling pathway.
pubmed:affiliation
Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.