ROLE OF COLLAGENOLYTIC METALLOPROTEINASES IN METASTASES

胶原蛋白金属蛋白酶在转移中的作用

• 批准号: 3796517
• 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/3796517
• 关键词: active sites; antibody; cell membrane; collagenase; colorectal neoplasms; enzyme complex; enzyme induction /repression; enzyme mechanism; enzyme structure; genetic regulation; human tissue; metalloenzyme; metastasis; neoplasm /cancer invasiveness; phorbols; protease inhibitor; stromelysin; transforming growth factors

In order to investigate the role of type IV collagenase in tumor invasion and metastases, we have focused on the multilevel regulation of this enzyme. These studies have shown that in contrast with other members of the collagenase enzyme family, the 72 kDa type IV collagenase mRNA levels are increased in response to TGFbeta1, are unaffected by the tumor promoting phorbol esters, and show elevated levels in colorectal 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 type IV collagenase enzyme, and which can be induced by pretreatment with phorbol esters of concanavalin A. This cellular activation mechanism does not affect other members of the collagenase gene family. Further characterization and purification of components of this activation mechanism are ongoing. We have studied the structure of the latent enzyme TIMP-2 complex through production of enzyme deletion mutants and enzyme inhibitor cross linking studies. These studies demonstrate that the 72 kDa type IV collagenase has at least two TIMP-2 binding domains. The principal binding domain is located in the C-terminal, hemopexin-like domain of the enzyme. This binding site is available in the latent enzyme form. The second binding site is at the enzyme active site and only becomes available following organomercurial mediated enzyme activation. Finally, antipeptide antibodies against the 92 kDa type IV collagenase, interstitial collagenase, stromelysin-1 and stromelysin-2 have been prepared and characterized.

目的探讨ⅳ型胶原酶在肿瘤侵袭中的作用