NOVEL RECEPTORS OF VITAMIN A IN THE CYTOPLASM

描述：在一个世纪的维生素A营养研究中，对营养的研究非常详细 关于行动机制的知识已经积累起来。然而，有几个方面 营养性维生素A缺乏症仍不能用主导的 通过维甲酸进行转录调控。特别是，对 许多人推测，由维生素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，通过显示 视黄醇和代谢物14-羟基-反式视黄醇(14HRR)结合 几种蛋白激酶C调节域的富含半胱氨酸的锌指结构域 异构体和其他丝氨酸/苏氨酸激酶。我们的假设是 维甲酸/锌指复合体在氧化还原过程中起可逆开关的作用 激活酶的激活。主要事件是所选择的半胱氨酸的氧化 由附近的维甲酸标记的残留物。类维A酸起到催化剂的作用 促进氧化。半胱氨酸中锌的释放与配位丧失 会导致构象状态的改变 导致其激活的PKC。因此，锌配位结构具有其 结合的维甲酸可以作为传感器和执行器，直接与 细胞质的氧化还原状态，使细胞维持稳定的水平 活性蛋白激酶C的活性以及对氧化应激的快速反应。有建议说 目的：研究视黄醇对氧化还原电位的影响。 氧化还原激活PKCα的可逆性(目标1)；研究化学 锌指与引起锌离子的氧化还原变化的关系 释放/结合(目标2)；通过以下方式研究氧化还原电位的微调 不同的维甲酸与锌指结合(目标3)；通过成像验证 体内维甲酸与PKC结合的技术(目标4)。这项研究将 将维生素A领域向前推进。此外，一种新的范式将是 创造了氧化还原调节--细胞的日常需求--如何与 一般的信号装置和新陈代谢的促进器 抄写。这些根本性的见解，将对炎症性 有助于理解活性氧如何促进癌症 进步。

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.