期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 278, 期 41, 页码 40364-40372出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M302999200
关键词
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资金
- NCI NIH HHS [CA89113, CA-82298] Funding Source: Medline
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.
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