NOVEL METALLOPROTEINASE INHIBITORS--ROLE IN TUMOR INVASION AND METASTASIS

新型金属蛋白酶抑制剂——在肿瘤侵袭和转移中的作用

• 批准号: 5200999
• 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/5200999
• 关键词: angiogenesis; basement membrane; biological signal transduction; blood brain barrier; cell cycle; cell growth regulation; cyclic AMP; fibroblasts; fibrosarcoma; genetic transcription; growth inhibitors; human tissue; membrane reconstitution /synthesis; metastasis; mitogens; neoplasm /cancer invasiveness; protein kinase A; protein sequence; receptor binding; stroke; tissue /cell culture; tissue inhibitor of metalloproteinases; vascular endothelium

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. Our studies have shown that TIMP-2 transcription is regulated independently of both TIMP-1 and TIMP-3. We have also demonstrated that TIMP-2 is anti-angiogenic. The mechanism for this effect is two fold; through inhibition of endothelial cell proliferation and blocking endothelial cell-mediated matrix proteolysis. TIMP-2 inhibits tumor cell invasion through reconstituted basement membranes in vitro, and this inhibitor demonstrates erythroid potentiating activity (EPA). TIMP-2 inhibits proteolytic opening of the blood brain barrier in hemorrhagic stroke models. In addition to their function as MMP inhibitors, a growing body of experimental evidence suggests that TIMPs behave as cytokines and stimulate cellular proliferation in the absence of other growth factors. In the presence of growth factors, however, TIMP-2 antagonizes the growth of cells. In order to understand the disparate effects of TIMP-2 on growth, the signal transduction mechanisms utilized by TIMP-2 was evaluated. The growth promoting effects are presumably mediated by putative TIMP receptors. Recent studies have demonstrated selective cell surface binding of TIMP-2 to HT-1080 cells that is not competed by TIMP-1. In the absence of serum or exogenous growth factors, rTIMP-2 mediates a mitogenic response in normal dermal fibroblasts and fibrosarcoma cells by stimulating adenylate cyclase to produce cAMP which, in turn, activates cAMP-dependent protein kinase (PKA). The increase in cAMP which may involve activation of a G- protein is required for proliferation. This is the first demonstration that TIMP-2 stimulates growth by activation of PKA. TIMP-2 peptides are currently being employed to map the precise location of this effect.

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。我们的研究表明 TIMP-2转录调控独立于TIMP-1和TIMP-2 TIMP-3。我们还证明了TIMP-2具有抗血管生成作用。 这种效应的机制是双重的；通过抑制 内皮细胞增殖与阻断内皮细胞介导的 基质蛋白分解。TIMP-2通过抑制肿瘤细胞侵袭 体外重组基底膜，以及这种抑制剂 显示红系增强活性(EPA)。TIMP-2抑制 出血性卒中血脑屏障蛋白水解性开放 模特们。 除了它们作为基质金属蛋白酶抑制剂的功能外，越来越多的 实验证据表明，TIMP作为细胞因子和 在没有其他生长的情况下刺激细胞增殖 各种因素。然而，在生长因子存在的情况下，TIMP-2 抑制细胞的生长。为了理解完全不同的 TIMP-2对生长的影响及其信号转导机制 对TIMP-2的利用进行了评价。促进生长的作用是 推测是由TIMP受体介导的。最近的研究表明 TIMP-2与HT-1080细胞表面的选择性结合 这是TIMP-1无法竞争的。在没有血清或外源性的情况下 生长因子rTIMP-2介导正常皮肤有丝分裂反应 刺激腺苷环化酶激活成纤维细胞和纤维肉瘤细胞 产生cAMP，cAMP进而激活cAMP依赖的蛋白激酶 (PKA)。CAMP的增加可能涉及G- 蛋白质是增殖所必需的。这是第一次 证明TIMP-2通过激活PKA促进生长。 TIMP-2多肽目前正被用来绘制精确的 此效果的位置。