Transcriptional Signaling by vitamin A

摘要 目前认为维生素A，视黄醇，是生物惰性的，并且其无数的生物功能是生物活性的。 由活性代谢物产生：视觉发色团11-顺式-视黄醛和视黄酸，它们调节 通过激活特定的核激素受体来表达基因。令人惊讶的是，我们的初步数据表明， 视黄醇本身就是一种转录调节因子视黄醇在血液循环中与血清视黄醇结合- 结合蛋白（RBP），但它必须在进入靶细胞之前与蛋白质解离。最近有 显示一种称为STRA 6的完整质膜蛋白结合RBP并介导RBP的摄取。 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， 作为一种转运蛋白，STRA 6是一种配体激活的细胞表面受体，其激活JAK/STAT途径， 响应于结合视黄醇-RBP。具体地说，数据表明，STRA 6与视黄醇结合的 RBP导致STAT的磷酸化和激活，这反过来又诱导特异性转录因子的转录。 STAT靶基因。本文提出的研究将解决视黄醇可以调节基因表达的假设。 通过激活由RBP/STRA 6/STAT途径介导的信号传导途径来转录。我们进一步 我拟阐明该通路参与调节脂质稳态和胰岛素反应 并控制细胞的生长和存活。这些研究的结果可能指向新的靶点， 糖尿病和癌症的治疗方法。

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.