Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells.
Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells.
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发表时间：
1999-12
期刊：
影响因子：
11.2
通讯作者：
Gangyong Li;R. Fridman;Hyeong‐Reh Choi Kim
中科院分区：
文献类型：
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作者：
Gangyong Li;R. Fridman;Hyeong‐Reh Choi Kim
对细胞存活至关重要的信号传导途径部分由细胞外基质的组成和完整性及其组分对特定细胞粘附受体的作用介导。锚定依赖性上皮细胞从其与ECM的关联中退出导致凋亡性细胞死亡。基质金属蛋白酶（matrix metalloproteinases，MMPs）及其抑制剂（tissue inhibitors，TIMPs）是细胞凋亡的重要调控因子。在这份报告中，我们调查是否bcl-2抑制凋亡涉及TIMP表达的调节。我们已经发现bcl-2过表达诱导乳腺上皮细胞系（MCF 10A、MCF 10AneoT、TG 3B和MCF-7）中TIMP-1的表达，而它对TIMP-2的表达没有影响。我们证明，TIMP-1抑制过氧化氢，阿霉素，或X射线照射诱导的细胞死亡。此外，TIMP-1过表达抑制MCF 10A细胞中细胞粘附丧失（失巢凋亡）后的凋亡，表明TIMP-1的抗凋亡活性不依赖于其稳定细胞-基质相互作用的能力。我们还发现TIMP-1的过度表达与黏着斑激酶的组成性激活有关，黏着斑激酶是一种已知对细胞存活途径至关重要的信号分子。
The signaling pathways critical for cell survival are mediated in part by the composition and integrity of the extracellular matrix and the action of its components on specific cell adhesion receptors. Withdrawal of anchorage-dependent epithelial cells from their association with ECM results in apoptotic cell death. Consistently, the matrix metalloproteinases (MMPs) or their inhibitors (TIMPs) have been suggested to regulate apoptosis. In this report, we investigated whether bcl-2 inhibition of apoptosis involves regulation of TIMP expression. We have found that bcl-2 overexpression induces TIMP-1 expression in breast epithelial cell lines (MCF10A, MCF10AneoT.TG3B, and MCF-7), whereas it has no effect on TIMP-2 expression. We demonstrated that TIMP-1 inhibits cell death induced by hydrogen peroxide, Adriamycin, or X-ray irradiation. In addition, TIMP-1 overexpression inhibits apoptosis after the loss of cell adhesion (anoikis) in MCF10A cells, suggesting that the antiapoptotic activity of TIMP-1 does not depend on its ability to stabilize cell-matrix interactions. We also showed that TIMP-1 overexpression is associated with constitutive activation of focal adhesion kinase, a signaling molecule known to be critical for the cell survival pathway.