Matrix metal loproteinase-1 associates with intracellular organelles and confers resistance to lamin A/C degradation during apoptosis
Matrix metal loproteinase-1 associates with intracellular organelles and confers resistance to lamin A/C degradation during apoptosis
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DOI：
10.1016/s0002-9440(10)62371-1
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发表时间：
2005-05-01
影响因子：
6
通讯作者：
Khaw, PT
中科院分区：
文献类型：
--
作者：
Limb, GA;Matter, K;Khaw, PT
自从基质金属蛋白酶（MMP）-1作为间质胶原酶首次被描述以来，在肿瘤、炎症和血管生成过程中，这种酶在细胞外基质重塑中具有重要意义。随着越来越多的证据显示基质金属蛋白酶在靶向非基质底物中的作用，在体外和体内发现的细胞内基质金属蛋白酶-1的偶然观察提示了基质金属蛋白酶-1可能对基本细胞功能如细胞分裂和细胞凋亡发挥作用的研究。在这里，我们首次表明MMP-1不仅具有细胞外功能，而且与线粒体和细胞核密切相关，并在细胞周期的有丝分裂期在细胞内积累。在诱导凋亡，MMP-1共定位与聚集的线粒体和周围的碎片核积累。与未处理的细胞相比，通过RNA干扰或用广泛的MMP抑制剂处理来抑制这种酶引起核纤层蛋白A的更快降解、半胱天冬酶的激活和DNA片段化。这些观察结果强烈表明，MMP-1的线粒体和细胞核的细胞内协会赋予抗凋亡，并可能解释这种酶与肿瘤细胞存活和扩散的众所周知的关联。
Since the first description of matrix metalloproteinase (MMP)-1 as an interstitial collagenase, great importance has been ascribed to this enzyme in extracellular matrix remodeling during tumoral, inflammatory, and angiogenic processes. As more evidence for the role of MMPs in targeting nonmatrix substrates emerges, casual observations that intracellular MMP-1 is found in vitro and in vivo prompt investigation of the role that MMP-1 may play on basic cell functions such as cell division and apoptosis. Here we show for the first time that MMP-1 not only has extracellular functions but that it is strongly associated with mitochondria and nuclei and accumulates within the cells during the mitotic phase of the cell cycle. On induction of apoptosis, MMP-1 co-localized with aggregated mitochondria and accumulated around fragmented nuclei. Inhibition of this enzyme by RNA interference or treatment with a broad MMP inhibitor caused faster degradation of lamin A, activation of caspases, and fragmentation of DNA when compared with untreated cells. These observations strongly suggest that intracellular association of MMP-1 to mitochondria and nuclei confers resistance to apoptosis and may explain the well-known association of this enzyme with tumor cell survival and spreading.