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因子家族(TIMP)新成员 家族)，我们称之为TIMP-2。TIMP-2与TIMP-2结合 72 kDa IV型胶原酶的潜伏期。最近的研究表明 到目前为止所有研究过的分泌72 kDa IV型病毒的细胞 胶原酶与TIMP-2形成复合体，分泌该酶。转化生长因子测试版 对这些细胞的处理导致TIMP-2mRNA的减少 文字记录水平。伴随着72 kDa IV型的诱导 胶原酶mRNA，这会导致酶抑制比的变化 有利于蛋白质的分解。这些研究还表明，TIMP-2 转录调控独立于TIMP-1和72 kDa IV型胶原酶。我们还证明了TIMP-2是 抗血管生成作用的机制是通过 抑制内皮细胞增殖。最后，我们展示了 TIMP-2通过重组基底膜抑制肿瘤细胞侵袭 体外培养的膜。

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.