NOVEL METALLOPROTEINASE INHIBITORS--ROLE IN TUMOR INVASION AND METASTASIS

我们已经分离并表征了一个完整的一级结构。 金属蛋白酶组织抑制剂家族的新成员 家族），我们称之为TIMP-2。 TIMP-2特异性结合于 潜伏形式的72 kDa IV型胶原酶。 最近的研究表明 迄今为止研究的所有分泌72 kDa IV型 胶原酶分泌这种酶作为与TIMP-2复合物。 TGFbeta 这些细胞的处理导致TIMP-2 mRNA的减少， 转录水平。 沿着诱导72 kDa IV型 胶原酶mRNA，这导致酶抑制剂比例的变化 有利于蛋白水解。 这些研究还表明，TIMP-2 转录的调节独立于TIMP-1和72 kDa的 IV型胶原酶。 我们还证明了TIMP-2是 抗血管生成，这种作用的机制是通过 抑制内皮细胞增殖。 最后，我们证明了 TIMP-2通过重建基底膜抑制肿瘤细胞侵袭 膜在体外。

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. TGFbeta treatment of these cells results in a decrease in the TIMP-2 mRNA transcript levels. Along with induction of the 72 kDa type IV collagenase mRNA, this results in a shift in the enzyme inhibitor ratio in favor of proteolysis. These studies have also 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 and that the mechanism for this effect is through inhibition of endothelial cell proliferation. Finally, we have shown that TIMP-2 inhibits tumor cell invasion through reconstituted basement membranes in vitro.