Transcriptional Signaling by vitamin A

摘要 目前人们认为维生素A，视黄醇在生物上是惰性的，它的各种生物学功能是 活性代谢物：视觉发色团11-顺式视黄醛和维甲酸，它们调节 通过激活特定的核激素受体进行基因表达。令人惊讶的是，我们的初步数据显示 视黄醇本身就是一种转录调节因子。视黄醇在血液中循环，与血清视黄醇结合- 结合蛋白(RBP)，但它必须在进入靶细胞之前从蛋白质中解离出来。那是最近的事 研究表明，一种称为STRA6的完整质膜蛋白与RBP结合并介导摄取 视黄醇进入细胞。然而，我们的初步结果表明，除了作为维生素A的功能外， 转运蛋白STRA6是一种配体激活的细胞表面受体，它激活了JAK/STAT通路。 对结合视黄醇-RBP的反应。具体地说，数据表明，STRA6与视黄醇结合 RBP导致STATS的磷酸化和激活，进而诱导特定的转录 统计目标基因。这里提出的研究将解决视黄醇可以调节基因的假说。 通过激活RBP/STRA6/STAT通路介导的信号通路进行转录。我们进一步 建议阐明其在调节脂质稳态和胰岛素反应中的作用 并控制细胞的生长和存活。这些研究的结果可能指向新的目标 治疗糖尿病和癌症的方法。

Abstract It is currently believed that vitamin A, retinol, is biologically inert and that its myriad of biological functions are exerted by active metabolites: the visual chromophore 11-cis-retinaldehyde, and retinoic acids, which regulate gene expression by activating specific nuclear hormone receptors. Surprisingly, our preliminary data suggest that retinol is a transcriptional regulator in its own right. Retinol circulates in blood bound to serum retinol- binding protein (RBP) but it must dissociate from the protein prior to entering target cells. It was recently shown that an integral plasma membrane protein termed STRA6 binds RBP and mediates the uptake of retinol into cells. Our preliminary results demonstrate however that, in addition to its function as a vitamin A transporter, STRA6 is a ligand-activated cell surface receptor which activates a JAK/STAT pathway in response to binding retinol-RBP. Specifically, the data indicate that, association of STRA6 with retinol-bound RBP results in phosphorylation and activation of STATs, which, in turn, induce the transcription of specific STAT target genes. Studies proposed here will address the hypothesis that retinol can regulate gene transcription by activating a signalling pathway mediated by an RBP/STRA6/STAT pathway. We further propose to elucidate its involvement of this pathway in regulation of lipid homeostasis and insulin responses and in control of cell growth and survival. The results of these studies may point at novel targets for therapeutic approaches in treatment of diabetes and cancer.