ROLE OF COLLAGENOLYTIC METALLOPROTEINASES IN METASTASES

胶原蛋白溶解金属蛋白酶在转移中的作用

• 批准号: 5200993
• 负责人: W G STETLER-STEVENSON
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5200993
• 关键词: bladder neoplasm; breast neoplasms; collagenase; colorectal neoplasms; concanavalin A; enzyme activity; enzyme biosynthesis; enzyme complex; enzyme induction /repression; enzyme mechanism; human tissue; metastasis; neoplasm /cancer invasiveness; ovary neoplasms; phorbols; thyroid neoplasm; tissue inhibitor of metalloproteinases; transforming growth factors; zymogens

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.

为了研究基质金属蛋白酶（MMP）在肿瘤细胞中的作用， 肿瘤的侵袭和转移，我们关注的是多层次的 这些酶的调节。 研究表明，与 MMP酶家族的其他成员，72 kDa明胶酶A水平是 增加的TGF β 1，不受肿瘤促进 佛波醇酯，并且在结肠直肠，乳腺， 甲状腺、卵巢和膀胱肿瘤组织与邻近组织相比， 正常粘膜组织。 我们发现了一种细胞激活 该机制是细胞表面相关的，并且对72 kDa的 明胶酶A酶，并且其可以通过用 佛波醇酯或伴刀豆球蛋白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的 明胶酶 我们现在已经证明， 明胶酶A/TIMP-2复合物和随后与推定的 TIMP-2受体是这种细胞激活的重要步骤 机制 此外，我们还研究了MMP-2的动力学特征。 和TIMP-2的生物合成，以确定何时何地形成 酶前体抑制剂复合物的发生。 这些结果表明 明胶酶A/TIMP-2复合物在结合 抑制剂介导该蛋白酶的细胞活化。