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，并且其无数的生物功能由活性代谢物发挥：视觉发色团11-顺式-视黄醇醛和视黄酸，其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因子。视黄醇在血液中循环，与血清视黄醇结合蛋白（RBP）结合，但在进入靶细胞之前必须与蛋白质解离。最近显示，一种称为STRA 6的整合质膜蛋白结合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，除了作为维生素A转运蛋白的功能外，STRA 6是一种配体激活的细胞表面受体，其响应于结合视黄醇-RBP而激活JAK/STAT途径。具体而言，数据表明，STRA 6与视黄醇结合的RBP的结合导致STAT的磷酸化和活化，这反过来又诱导特异性STAT靶基因的转录。这里提出的研究将解决的假设，视黄醇可以调节基因转录通过激活RBP/STRA 6/STAT途径介导的信号通路。我们进一步建议阐明其参与的这一途径的调节脂质稳态和胰岛素反应，并在控制细胞的生长和存活。这些研究的结果可能为糖尿病和癌症的治疗方法指明新的靶点。 公共卫生相关性：胰岛素抵抗和糖尿病是流行病比例的全球公共卫生问题，并且迫切需要阐明这些疾病的分子基础和鉴定新的治疗靶点。维生素A（视黄醇）存在于血液中，与一种称为视黄醇结合蛋白（RBP）的蛋白质结合，并通过一种称为STRA 6的转运蛋白从这种蛋白质中摄取到靶细胞中。最近提出RBP是诱导胰岛素抵抗的致病因素，但尚不清楚该蛋白质如何发挥这种作用。通过我们的初步观察，RBP抑制胰岛素作用的机制。这些数据表明，维生素A结合的RBP与STRA 6的结合导致信号级联的激活，其最终导致抑制胰岛素信号传导的基因表达的上调。因此，研究结果表明，维生素A在调节基因表达方面具有以前未被怀疑的功能。拟议的研究将检查维生素A的新活性在调节脂质代谢和胰岛素敏感性以及控制细胞生长和存活中的参与。这些研究的结果可能为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. PUBLIC HEALTH RELEVANCE: Insulin resistance and diabetes are global public health problems of epidemic proportions and there is an urgent need for elucidating the molecular basis of these diseases and for identifying novel therapeutic targets. Vitamin A (retinol) is present in blood bound to a protein termed retinol binding protein (RBP) and is taken up from this protein into target cells by a transporter called STRA6. It was recently suggested that RBP is a causative factor in the induction of insulin resistance but it is unknown how the protein may exert such an effect. A mechanism through which RBP inhibits insulin action is suggested by our preliminary observations. These data show that binding of vitamin A-bound RBP to STRA6 results in activation of a signalling cascade that culminates in upregulation of the expression of genes that inhibit insulin signalling. The findings thus indicate that vitamin A possesses a previously unsuspected function in regulation of gene expression. Proposed studies will examine the involvement of the novel activity of vitamin A in regulation lipid metabolism and insulin sensitivity as well as 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.