NOVEL METALLOPROTEINASE INHIBITORS--ROLE IN TUMOR INVASION AND METASTASIS

我们分离并鉴定了一个新的 金属蛋白酶组织抑制剂家族（TIMP家族）成员 我们称之为TIMP-2。 TIMP-2特异性结合潜伏型 72 kDa的IV型胶原酶。 最近的研究表明，所有 迄今为止所研究的分泌72 kDa IV型胶原酶的细胞 分泌这种酶作为TIMP-2的复合物。 我们的研究显示 TIMP-2转录的调节独立于TIMP-1和72 kDa IV型胶原酶。 我们还证明了TIMP-2是 抗血管生成。 这种作用的机制可能是通过抑制 除了抑制内皮细胞增殖外， 细胞介导的基质蛋白水解。 我们已经证明TIMP-2抑制肿瘤生长， 细胞通过体外重建的基底膜侵入， 该抑制剂显示红细胞增强活性（EPA）。 最近的研究已经针对克隆人TIMP-2基因， 确定其染色体定位。 两个人TIMP-2基因组克隆 已经获得了大约9和12 kb。 该基因似乎是 单拷贝，定位于人染色体17 q22 -25。 我们已经检查了TIMP-2蛋白的结构，并定位了TIMP-2的表达。 金属蛋白酶抑制结构域位于分子的N末端一半。 进一步的亚定位已经尝试使用合成肽的方法， .

We have isolated and characterized the complete primary structure of a new member of the tissue inhibitor of metalloproteinase family (TIMP family) which we refer to as TIMP-2. TIMP-2 binds specifically to the latent form of the 72 kDa type IV collagenase. Recent studies have shown that all cells studied to date which secrete the 72 kDa type IV collagenase enzyme secrete this enzyme as a complex with TIMP-2. Our studies have shown that TIMP-2 transcription is regulated independently of both TIMP-1 and the 72 kDa type IV collagenase enzyme. We have also demonstrated that TIMP-2 is anti-angiogenic. The mechanism for this effect may be through inhibition of endothelial cell proliferation in addition to inhibiting endothelial cell mediated matrix proteolysis. We have shown that TIMP-2 inhibits tumor cell invasion through reconstituted basement membranes in vitro, and that this inhibitor demonstrates erythroid potentiating activity (EPA). Recent studies have been directed at cloning the human TIMP-2 gene and determining its chromosomal localization. Two human TIMP-2 genomic clones of approximately 9 and 12 kb have been obtained. The gene appears to be single copy and is localized on human chromosome 17q22-25. We have examined the TIMP-2 protein structure and have localized the metalloprotease inhibitory domain to the N-terminal half of the molecule. Further sublocalization has been attempted using a synthetic peptide approa .