FUNCTION AND REGULATION OF LATENT FORMS OF TGF-BETA

TGF-β 潜在形式的功能和调节

• 批准号: 3853451
• 负责人: L M WAKEFIELD
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 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/3853451
• 关键词: cell growth regulation; growth inhibitors; hormone regulation /control mechanism; inhibitor /antagonist; laboratory rat; neoplasm /cancer pharmacology; peptides; protein biosynthesis; protein purification; protein sequence; protein structure function; radiotracer; secretion; steroid hormone; tissue /cell culture; transforming growth factors

Under normal physiological conditions, TGF-betas are synthesized predominantly in biologically latent forms. We have purified recombinant latent TGF-beta and radioiodinated it for use in pharmacokinetic studies. We have demonstrated that the latent complex has a much longer plasma half-life in rats than active TGFbetal, and a very different tissue distribution. This suggests that latent TGF-betal may be the form of choice for clinical use. We have further shown that certain members of the steroid hormone superfamily can induce the secretion of active, rather than latent, TGF-betal in specific target tissues, and we propose that this local induction of an endogenous inhibitor of cell growth by steroids could be exploited to develop a new pharmacology of cancer prevention or treatment. In addition, the possibility that active TGF-beta might interact with its cognate receptor intracellularly was investigated by the use of recombinant DNA techniques to add an endoplasmic reticulum retention sequence on to both active and latent TGF-beta. The results indicated that addition of any C-terminal extension to the TGF-betal molecule interferes with biosynthetic processing and destroys biological activity. Thus strategies to develop antagonists or superantagonists of TGF-beta should avoid modification of this region.

在正常生理条件下，转化生长因子-β被合成 主要以生物潜伏的形式存在。我们已经纯化了重组人 潜伏的转化生长因子-β，并将其放射性碘化，用于药代动力学研究。 我们已经证明了潜伏的复合体有更长的血浆 大鼠的半衰期比活性的TGFbetal，和组织有很大的不同 分发。这提示潜伏的转化生长因子-β1可能是 临床使用的选择。我们进一步表明，某些成员 类固醇激素超家族可以诱导分泌活性物质， 而不是在特定的靶组织中潜伏的转化生长因子-β1，我们建议 这种内源性细胞生长抑制因子的局部诱导 类固醇可以被用来开发治疗癌症的新药理 预防或治疗。此外，活跃的可能性 转化生长因子-β可能与其同源受体在细胞内相互作用。 通过使用重组DNA技术添加一个 内质网保留序列对活性和潜伏期的影响 转化生长因子-β。结果表明，添加任何C-末端 延伸的转化生长因子-β分子干扰生物合成 加工并破坏生物活性。从而制定发展战略 转化生长因子-β拮抗剂或超拮抗剂应避免修饰 这个地区。