Matrix metalloproteinase-26 is associated with estrogen-dependent malignancies and targets α1-antitrypsin serpin
Matrix metalloproteinase-26 is associated with estrogen-dependent malignancies and targets α1-antitrypsin serpin
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DOI：
10.1158/0008-5472.can-04-3019
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发表时间：
2004-12-01
期刊：
影响因子：
11.2
通讯作者：
Strongin, AY
中科院分区：
文献类型：
--
作者：
Li, W;Savinov, AY;Strongin, AY
蛋白酶通过对调节蛋白进行蛋白水解修饰来控制细胞行为并影响许多生物过程。本文的目的是描述基质金属蛋白酶 (MMP)-26 的新颖、重要功能。 α-抗胰蛋白酶（AAT）是一种丝氨酸蛋白酶抑制剂，其主要功能是调节中性粒细胞/白细胞弹性蛋白酶的活性。由于肺部 AAT 缺乏而导致的抗蛋白酶活性不足是导致早发性肺气肿的一个因素。我们最近发现 AAT 可以被一种新型金属蛋白酶 NIMP-26 有效裂解，该酶表现出非常规的 PH(81)CGVPD Cys 开关基序，并在细胞和组织中自动催化激活。巨噬细胞和多形核白细胞中 MMP-26 的表达升高支持 MMP-26 在 AAT 裂解和炎症中的功能作用。我们已经证明了 MMP-26 表达与雌激素依赖性的直接功能联系，并证实了 MMP-26 启动子中雌激素反应元件的存在。肿瘤细胞系和活检标本微阵列的免疫染色证实细胞/组织中MMP-26和AAT存在负相关性。 MMP-26 在雌激素依赖性肿瘤中的表达可能有助于 AAT 失活，随后释放 Ser 蛋白酶活性，并且由于这些生化事件，促进基质破坏和恶性进展。总之，我们假设 NIMP-26 通过裂解和灭活 AAT 丝氨酸蛋白酶抑制剂，作为一种独特的功能链接来调节雌激素依赖性肿瘤中丝氨酸和金属蛋白酶之间的协调相互作用。
Proteases exert control over cell behavior and affect many biological processes by making proteolytic modification of regulatory proteins. The purpose of this paper is to describe novel, important functions of matrix metalloproteinase (MMP)-26. alphal-Antitrypsin (AAT) is a serpin, the primary function of which is to regulate the activity of neutrophil/leukocyte elastase. Insufficient antiprotease activity because of AAT deficiency in the lungs is a contributing factor to early-onset emphysema. We recently discovered that AAT is efficiently cleaved by a novel metalloproteinase, NIMP-26, which exhibits an unconventional PH(81)CGVPD Cys switch motif and is autocatalytically activated in cells and tissues. An elevated expression of MMP-26 in macrophages and polymorphonuclear leukocytes supports the functional role of MMP-26 in the AAT cleavage and inflammation. We have demonstrated a direct functional link of MMP-26 expression with an estrogen dependency and confirmed the presence of the estrogen-response element in the MMP-26 promoter. Inummostaining of tumor cell lines and biopsy specimen microarrays confirmed the existence of the inverse correlations of MMP-26 and AAT in cells/tissues. An expression of MMP-26 in the estrogen-dependent neoplasms is likely to contribute to the inactivation of AAT, to the follow-up liberation of the Ser protease activity, and because of these biochemical events, to promote matrix destruction and malignant progression. In summary, we hypothesize that NIMP-26, by cleaving and inactivating the AAT serpin, operates as a unique functional link that regulates a coordinated interplay between Ser and metalloproteinases in estrogen-dependent neoplasms.