NOVEL RECEPTORS OF VITAMIN A IN THE CYTOPLASM

细胞质中维生素 A 的新型受体

• 批准号: 6230486
• 负责人: ULRICH G HAMMERLING
• 金额: $ 33.99万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6230486
• 关键词: biological signal transduction; cysteine; cytoplasm; enzyme activity; intermolecular interaction; nutrition related tag; oxidative stress; protein kinase C; retinoid binding proteins; retinoids; tissue /cell culture; zinc

DESCRIPTION: During a century of vitamin A research in nutrition much detailed knowledge on the mechanism of action has accrued. Yet several aspects of nutritional vitamin A deficiency remain unexplained by the reigning paradigm of transcription control via retinoic acid. In particular, the regulation of cytoplasmic events by vitamin A and metabolites, postulated by many, has remained elusive. We have identified a family of likely receptors by showing that retinol and the metabolite, 14-hydroxy-retro-retinol (14HRR), bind the cysteine-rich, zinc-finger subdomains of the regulatory domains of several PKC isoforms and other serine/threonine kinases. Our hypothesis is that the retinoid/zinc-finger complex functions as reversible switch during redox activation of the kinase. The primary event is oxidation of selected cysteine residues tagged by a retinoid bound nearby. The retinoid acts as catalyst to facilitate oxidation. Release of zinc from cysteines and loss of coordination of an otherwise rigid structure leads to the changed conformational state in PKC that ushers in its activation. Thus, a zinc-coordinated structure with its bound retinoid could serve as a sensor and actuator, directly linked to the redox state of the cytoplasm, allowing cells to maintain a steady-state level of active PKC as well as to respond quickly to oxidative stress. It is proposed to determine the influence of retinol on the redox potential and the reversibility of redox activation of PKC alpha (Aim #1); to study the chemistry of the zinc finger with respect to redox changes that cause Zn2+ release/binding (Aim # 2); to investigate the fine-tuning of redox potential by different retinoids bound to the zinc-finger (Aim # 3); to verify by imaging techniques the binding of retinoids to PKC in vivo (Aim # 4). The study will move the field of vitamin A forward. Furthermore, a new paradigm would be created how redox regulation, an every-day requirement for cells, connects to the general signalling apparatus and on to the actuators of metabolism and transcription. These fundamental insights, will impact on inflammatory processes and contribute to understand how reactive oxygen promotes cancer progression.

描述：在一个世纪的维生素A营养研究中，非常详细 关于作用机制的知识已经积累。然而， 营养性维生素A缺乏症仍然无法解释的统治范式， 通过视黄酸进行转录控制。特别是， 许多人假设，维生素A和代谢物引起的细胞质事件， 仍然难以捉摸我们已经确定了一个可能的受体家族， 视黄醇和代谢产物14-羟基-反视黄醇（14 HRR）结合 富含半胱氨酸的几种PKC调节结构域的锌指亚结构域 同工型和其它丝氨酸/苏氨酸激酶。我们的假设是 类维生素A/锌指复合物在氧化还原过程中起可逆开关作用 激酶的激活。主要事件是选择性半胱氨酸的氧化 被附近的类维生素A标记的残基。类维生素A作为催化剂， 促进氧化。锌从半胱氨酸的释放和配位的丧失 导致了构象状态的改变， PKC，引导其激活。因此，锌配位结构及其 结合类维生素A可以作为传感器和执行器，直接连接到 氧化还原状态的细胞质，使细胞保持稳定状态的水平 以及对氧化应激的快速反应。拟 以确定视黄醇对氧化还原电位和 PKC α氧化还原活化的可逆性（目的#1）;研究化学 锌指的氧化还原变化，导致Zn 2 + 释放/结合（目标#2）;研究氧化还原电位的微调， 与锌指结合的不同类维生素A（目标3）;通过成像进行验证 技术类维生素A在体内与PKC的结合（目的#4）。这项研究将 推动维生素A领域的发展此外，一个新的范例将是 创造了氧化还原调节，细胞的日常要求，如何连接到 一般的信号装置和新陈代谢的执行器， 转录。这些基本的见解，将影响炎症 有助于了解活性氧如何促进癌症 进展