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: 3813421
• 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/3813421
• 关键词: binding proteins; collagen; collagenase; colon neoplasms; complementary DNA; enzyme induction /repression; enzyme mechanism; enzyme structure; enzyme substrate; fibronectins; gelatin; gene expression; genetic manipulation; genetic transcription; human tissue; metalloenzyme; metalloproteins; metastasis; molecular cloning; molecular oncology; neoplasm /cancer invasiveness; nucleic acid probes; protein purification; protein structure function; synthetic peptide

In order to investigate the role of type IV collagenase in tumor invasion and metastases, we have undertaken the purification, molecular cloning, enzymatic characterization, and the study of structure-function correlation of this 72 kDa metalloproteinase. We have also studied the binding of type IV collagenase to both type IV collagen and gelatin. These studies have demonstrated that enzyme binding to these substrates is independent of metal atoms and can be competed by fibronectin and fibronectin-gelatin binding domain peptides. Recent studies have focused on the transcriptional regulation of the 72 kDa collagenase Iv enzyme in both normal and human tumor cell lines as well as human tumor tissues. These studies have shown that the 72 kDa collagenase is unique among the members of the matrix metalloproteinase enzymes in the manner of its regulation by various cytokines. Also, the 72 kDa collagenase IV probes shows elevated levels in colorectal tumor tissues when compared with adjacent normal mucosa tissue. In expanding this project, we have also cloned and sequenced the human tumor cell interstitial collagenase. The tumor enzyme was found to be identical to the fibroblast collagenase, thus demonstrating definitively and for the first time that ductal epithelial cells are capable of producing this enzyme.

为了研究IV型胶原酶在肿瘤侵袭中的作用 和转移，我们进行了纯化、分子克隆、 酶表征以及结构-功能相关性研究 这种 72 kDa 金属蛋白酶。我们还研究了类型的绑定 IV 胶原酶可分解 IV 型胶原蛋白和明胶。这些研究有 证明酶与这些底物的结合独立于 金属原子，可与纤连蛋白和纤连蛋白明胶竞争 结合域肽。最近的研究主要集中在转录 正常人和人类中 72 kDa 胶原酶 Iv 的调节 肿瘤细胞系以及人类肿瘤组织。这些研究表明 72 kDa 胶原酶在基质成员中是独一无二的 金属蛋白酶的多种调节方式 细胞因子。此外，72 kDa 胶原酶 IV 探针显示， 结直肠肿瘤组织与邻近的正常粘膜组织相比。 在扩展这个项目的过程中，我们还对人类进行了克隆和测序 肿瘤细胞间质胶原酶。发现肿瘤酶是 与成纤维细胞胶原酶相同，从而明确证明 导管上皮细胞首次能够 产生这种酶。