Transcriptional signalling by vitamin A

描述（由申请人提供）：目前认为维生素A视黄醇是生物惰性的，其无数的生物功能是由活性代谢物发挥的：视觉发色团11-顺式视黄醛和视黄酸，它们通过激活特定的核激素受体来调节基因表达。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剂。视黄醇与血清视黄醇结合蛋白（RBP）结合在血液中循环，但在进入靶细胞之前必须与该蛋白分离。最近的研究表明，一种称为STRA6的整体质膜蛋白结合RBP并介导视黄醇进入细胞的摄取。然而，我们的初步结果表明，STRA6除了作为维生素a转运体的功能外，还是一种配体激活的细胞表面受体，在与视黄醇- rbp结合时激活JAK/STAT通路。具体来说，数据表明STRA6与视黄醇结合的RBP的关联导致STATs的磷酸化和激活，进而诱导特定STAT靶基因的转录。本文提出的研究将解决视黄醇通过激活RBP/STRA6/STAT通路介导的信号通路来调节基因转录的假设。我们进一步建议阐明其参与脂质稳态和胰岛素反应的调节以及细胞生长和存活的控制。这些研究的结果可能为治疗糖尿病和癌症的治疗方法指明新的靶点。

DESCRIPTION (provided by applicant): 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.