METABOLIC CONTROL PROINSULIN BIOSYNTHESIS TRANSLATION

代谢控制胰岛素原生物合成翻译

• 批准号: 2151642
• 负责人: Christopher J Rhodes
• 金额: $ 11.66万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-15 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2151642
• 关键词: METABOLIC; CONTROL; PROINSULIN; BIOSYNTHESIS; TRANSLATION

DESCRIPTION (Adapted from the Applicant's Abstract): This is a proposal to examine in detail the mechanisms underlying the translational regulation of proinsulin biosynthesis in the islet beta cells. Previous studies have established that proinsulin and several other proteins of the beta cell are translationally up-regulated by glucose by a rapidly- acting activating mechanism that does not require increased synthesis of mRNA. Translational control by glucose is selective and effects principally proinsulin and other proteins such as the convertases PC3, and possibly PC2, that are involved in processing proinsulin, as well as other unidentified lower-abundance proteins. Previous studies have indicated that translational stimulation is accompanied by increased mobilization of insulin RNA to the membrane-bound form on the rough endoplasm reticulum (RER), indicating that the rate of translational initiation is enhanced by glucose. Other studies have indicated that the rate of translational elongation may also be stimulated and that glucose does in fact result in minor degrees of enhancement of total islet protein biosynthesis, while proinsulin biosynthesis is increased by factors of 10-20 fold. Thus far efforts to determine how the selective turn-on of insulin messenger translation is effected have only been partially successful. It has been suggested that it may be due to enhanced SRP/SRP receptor interaction but there are strong indications that this may not be a sufficiently specific mechanism. The applicant proposes a new approach to this problem through investigation of potential regulatory protein binding stem-loop structures in the 5' upstream region of the insulin mRNA and those of other glucose-stimulated or non-stimulated proteins to examine the possibility that stimulation results from specific protein-RNA interactions similar to these involved in the control of ferritin biosynthesis by iron in the liver. Other studies will be directed toward examination of the role of protein phosphorylation/dephosphorylation mediated by PKA and PKC in regulating initiation of protein translation. The ultimate goal will be to elucidate the role of glucose metabolism, protein kinases and related factors in the rapid regulation of proinsulin biosynthesis in the beta cell and/or a model transformed beta cell line - the MIN6 line.

描述（改编自申请人的摘要）：这是一项提案 详细检查翻译背后的机制 胰岛β细胞中胰岛素原生物合成的调节。以前的 研究表明，胰岛素原和其他几种蛋白质 β细胞通过葡萄糖的快速翻译上调 不需要增加合成的作用激活机制 mRNA。葡萄糖的翻译控制具有选择性和影响 主要是胰岛素原和其他蛋白质，例如转化酶 PC3， 可能还有 PC2，参与胰岛素原的加工，以及 其他未鉴定的低丰度蛋白质。 之前的研究有 表明翻译刺激伴随着增加 将胰岛素 RNA 动员到粗糙表面的膜结合形式 内质网（RER），表明翻译率 葡萄糖可增强引发作用。其他研究表明， 平移延伸率也可能受到刺激，并且葡萄糖 事实上确实导致总胰岛的小程度增强 蛋白质生物合成，而胰岛素原生物合成则增加 10-20倍的因素。到目前为止，我们正在努力确定如何选择性地 胰岛素信使翻译的开启仅受到影响 部分成功。有人提出，这可能是由于 增强 SRP/SRP 受体相互作用，但有强烈的迹象 这可能不是一个足够具体的机制。申请人 通过调查提出了解决该问题的新方法 5' 中潜在的调节蛋白结合茎环结构 胰岛素 mRNA 的上游区域和其他葡萄糖刺激的上游区域 或非刺激蛋白质来检查刺激的可能性 与所涉及的类似的特定蛋白质-RNA 相互作用的结果 通过肝脏中的铁来控制铁蛋白的生物合成。其他 研究将旨在检查蛋白质的作用 PKA 和 PKC 介导的磷酸化/去磷酸化调节 蛋白质翻译的起始。最终目标将是阐明 葡萄糖代谢、蛋白激酶及相关因素在 β细胞中胰岛素原生物合成的快速调节和/或 模型转化的 β 细胞系 - MIN6 系。