ROLE OF COLLAGENOLYTIC METALLOPROTEINASES IN METASTASES

为探讨IV型胶原酶在肿瘤侵袭中的作用 和转移，我们已经进行了纯化，分子克隆， 酶的性质及其构效关系的研究 这个72 kDa的金属蛋白酶。我们还研究了类型的绑定 IV型胶原酶可以同时作用于IV型胶原和明胶。这些研究已经 证明了酶与这些底物的结合不依赖于 金属原子，可与纤维连接蛋白和纤维连接蛋白-明胶竞争 结合域肽。最近的研究主要集中在转录方面。 正常人和人72 kDa胶原酶IV酶的调节 肿瘤细胞系以及人类肿瘤组织。这些研究表明 72 kDa胶原酶在基质成员中是独一无二的 金属蛋白酶对多种酶的调节作用 细胞因子。此外，72 kDa胶原酶IV探针显示 结直肠肿瘤组织与邻近正常黏膜组织比较。 在扩大这个项目的过程中，我们还克隆了人类 肿瘤细胞间质胶原酶。肿瘤酶被发现是 与成纤维细胞胶原酶相同，从而明确表明 这是第一次导管上皮细胞能够 产生这种酶。

In order to investigate the role of type IV collagenase in tumor invasion and metastases, we have undertaken the purification, molecular cloning, enzymatic characterization, and the study of structure-function correlation of this 72 kDa metalloproteinase. We have also studied the binding of type IV collagenase to both type IV collagen and gelatin. These studies have demonstrated that enzyme binding to these substrates is independent of metal atoms and can be competed by fibronectin and fibronectin-gelatin binding domain peptides. Recent studies have focused on the transcriptional regulation of the 72 kDa collagenase Iv enzyme in both normal and human tumor cell lines as well as human tumor tissues. These studies have shown that the 72 kDa collagenase is unique among the members of the matrix metalloproteinase enzymes in the manner of its regulation by various cytokines. Also, the 72 kDa collagenase IV probes shows elevated levels in colorectal tumor tissues when compared with adjacent normal mucosa tissue. In expanding this project, we have also cloned and sequenced the human tumor cell interstitial collagenase. The tumor enzyme was found to be identical to the fibroblast collagenase, thus demonstrating definitively and for the first time that ductal epithelial cells are capable of producing this enzyme.