Tissue inhibitor of metalloproteinase-1 protects XXXX breast epithelial cells against intrinsic apoptotic cell death via the focal adhesion kinase/ @entity4357 3-kinase and MAPK signaling pathway.

@entity1 @entity1552 @entity2228 @entity535 @entity2843 @entity866 @entity1889 @entity4357
Tissue inhibitor of metalloproteinase ( @entity2843 ) is a natural protease inhibitor of matrix metalloproteinases (MMPs). Recent studies revealed a novel function of @entity2843 as a potent inhibitor of apoptosis in @entity1 cells. However, the mechanisms by which @entity2843 exerts its anti-apoptotic effect are not understood. Here we show that @entity2843 activates cell survival signaling pathways involving focal adhesion kinase, @entity4357 3-kinase, and ERKs in @entity1 breast epithelial cells to @entity2843 . @entity2843 -activated cell survival signaling down-regulates caspase-mediated classical apoptotic pathways induced by a variety of stimuli including anoikis, @entity866 exposure, and growth factor withdrawal. Consistently, down-regulation of @entity2843 expression greatly enhances apoptotic cell death. In a previous study, substitution of the second @entity535 residue @entity1889 for @entity2228 in @entity2843 , 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 @entity2843 is dependent on MMP inhibition. Here we show that the same mutant inhibits apoptosis of @entity1 breast epithelial cells, suggesting different mechanisms of @entity2843 regulation of apoptosis depending on cell types. Neither @entity1552 nor a synthetic MMP inhibitor protects breast epithelial cells from intrinsic apoptotic cell death. Furthermore, @entity2843 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 @entity2843 in @entity1 breast epithelial cells through @entity2843 -specific signal transduction pathways.
