Lipid Growth Factor for Normal and Malignant B Cells

维生素A缺乏的多效性症状包括明显的免疫缺陷。在过去的十年中，我们的团队已经定义了一个组织培养模型，表明细胞的生存/死亡决定是由视黄醇调节的，已经确定了几种新的视黄醇代谢物，对淋巴细胞的生存很重要，并解决了它们的结构。14-羟基复古视黄醇（HRR）是类维甲酸的原型，支持淋巴细胞存活，而无氢视黄醇（AR）最常诱导细胞凋亡。这两种反转录类维生素a都可以追溯到无脊椎动物的进化过程，这意味着它们具有非常基本的生物学作用。相比之下，维甲酸是脊椎动物的发明。在最后的资助期间，我们已经确定了丝氨酸/苏氨酸激酶，cRaf和PKC，作为逆转录类维生素a的主要受体。结合发生在这些激酶共有的富含半胱氨酸的区域，并且结合的视黄醇和HRR增强了氧化剂对磷酸转移酶活性的激活。我们已经制定了工作假设，即cys结构域作为类维甲酸调节的氧化还原开关起作用。类维生素a作为催化剂，针对特定的半胱氨酸进行选择性氧化。这项工作将试图确定cRaf激活周期中发生氧化还原激活的关键步骤（AIM编号1），定义氧化cys结构域的化学变化，以及结合的类维生素a产生的氧化还原电位的可能变化（AIM编号2），并确定正在氧化的精确半胱氨酸残基。如果得到证实，新的范式将导致对氧化还原活化如何有效靶向信号分子的理解。氧化还原调节作为免疫细胞在先天和适应性免疫反应中的控制因素，已被越来越多地接受。类维生素a的重要性在于它们能够微调氧化还原信号网络。不同类维生素a在氧化还原调控方面的显著差异，特别是我们已经证明的AR阻断氧化还原信号的能力，也可能转化为癌症治疗。

The pleotropic symptoms of Vitamin A deficiency include a marked immune deficiency. During the past decade our group has defined a tissue culture model, has shown that cell survival/death decisions are regulated by retinol, has identified several novel retinol metabolites important for lymphocyte survival, and has solved their structure. 14-hydroxy retro- retinol (HRR) is the prototype of agonistically acting retinoids, supporting lymphocyte survival, whereas anhydroretinol (AR) most often induces apoptosis. Both retro-retinoids can be traced fa br back in evolution to invertebrates, implying a very basic biological role. By contrast, retinoic acid is an invention of vertebrates. During the last grant period we have identified serine/threonine kinases, cRaf and PKC, as the principal receptors of retro-retinoids. Binding occurs at high affinity at the cysteine-rich domain that these kinases share in common, and bound retinol and HRR enhance the activation of phosphotransferase activity by oxidizing agents. We have formulated the working hypothesis that the cys domain functions as a retinoid-regulated redox switch. Retinoids act as catalysts to target special cysteines for selective oxidation. The proposed work will seek to identify the crucial step in the cRaf activation cycle where redox activation occurs (AIM number 1), to define the chemical changes in the oxidized cys domain, and the possible changes in redox potential created by bound retinoids (AIM number 2), and to identify the precise cysteine residues undergoing oxidation. If substantiated the new paradigm will lead to an understanding of how redox activation can be targeted effectively to signaling molecules. Redox regulation is increasingly accepted as controlling factor of immune cells in innate and adaptive immune reactions. The significance of retinoids lies in their capacity to fine-tune this redox signaling network. The marked differences in redox regulation among different retinoids, especially the capacity in AR to block redox signaling that we have demonstrated, may also allow translation into cancer therapy.