ROLE OF COLLAGENOLYTIC METALLOPROTEINASES IN METASTASES

为探讨基质金属蛋白酶(MMPs)在心肌梗死中的作用。 肿瘤的侵袭和转移，我们已经关注了多个层面 对这些酶的调节。研究表明，与 基质金属蛋白酶家族的其他成员，72 kDa明胶酶A水平为 增加对TGFbeta1的反应，不受促癌作用的影响 佛波醇酯，并显示结直肠，乳房， 甲状腺、卵巢和膀胱癌组织与癌旁组织的比较 正常粘膜组织。我们已经确认了一种细胞激活 72 kDa与细胞表面相关和特异的机制 明胶酶：一种酶，可通过用 佛波酯或刀豆蛋白A这种细胞激活机制 不影响胶原酶基因家族的其他成员。这 激活机制似乎需要细胞表面结合 明胶酶A酶。我们现在已经演示了 孕激素酶A/TIMP-2复合体和随后与推测的 TIMP-2受体是这种细胞激活的重要步骤 机制。此外，我们还对基质金属蛋白酶-2的动力学进行了表征 和TIMP-2的生物合成，以确定形成的时间和地点 酶原-抑制物复合体的发生。这些结果表明， 孕激素酶A/TIMP-2复合体在与 抑制剂介导了该酶的细胞激活。

In order to investigate the role of matrix metalloproteinases (MMP) in tumor invasion and metastases, we have focused on the multilevel regulation of these enzymes. Studies have shown that in contrast with other members of the MMP enzyme family, 72 kDa gelatinase A levels are increased in response to TGFbeta1, are unaffected by the tumor promoting phorbol esters, and show elevated levels in colorectal, breast, thyroid, ovarian and bladder tumor tissues when compared with adjacent normal mucosa tissues. We have identified a cellular activation mechanism which is cell surface associated and specific for the 72 kDa gelatinase A enzyme, and which can be induced by pretreatment with phorbol esters or concanavalin A. This cellular activation mechanism does not affect other members of the collagenase gene family. This activation mechanism appears to require cell surface binding of the gelatinase A enzyme. We have now demonstrated that formation of the progelatinase A/TIMP-2 complex and subsequent binding to a putative TIMP-2 receptor are important steps in this cellular activation mechanism. In addition, we have characterized the kinetics of MMP-2 and TIMP-2 biosynthesis in order to determine when and where formation of the proenzyme-inhibitor complex occurs. These results suggest that the progelatinase A/TIMP-2 complex is unique in that binding of the inhibitor mediates the cellular activation of this protease.