Mechanisms involved in the induction of cell adhesion by hypoxia inducible factor

缺氧诱导因子诱导细胞粘附的机制

基本信息

批准号：
17590258
负责人：
KANNAGI Reiji
金额：
$ 2.3万
依托单位：
Aichi Cancer Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Hypoxia figures heavily in pathophysiology of wide variety of diseases. In this research project we focused on induction mechanisms of genes encoding cell adhesion molecules by hypoxia. We found cell adhesion is markedly enhanced under hypoxic conditions. Transcriptional induction of genes for cell adhesion molecules by hypoxia is mediated mainly by a transcription factor, HIF (hypoxia inducible factor). As most cell adhesion molecules have carbohydrate side chains terminated by sialic acid residues, we focused on the effect of hypoxia on sialic acid metabolism. The cellular amount of sialic acid showed a significant increase under hypoxia, and this led to enhanced cell adhesion mediated by cell surface glycans carrying sialic acid residues. This was conferred by transcriptional induction of the gene for a sialic acid transporter, called Sialin. Transcription of genes for some sialyltransferases including ST3O was also enhanced by hypoxia, in addition to that of Sialin. HIF induced transcription of these genes, in some cases through collaboration with other transcription factors, and in some other cases solely by the action of HIF. It had been generally accepted that the cellular sialic acid pool is provided by de novo synthesis of sialic acid, but our present results indicated that incorporation of sialic acid through sialic acid transporter system also play an important role in supplying sialic acid residues required for synthesis of cell surface sialylated glycans. Hypoxia-induced Sialin transcription affected not only the synthesis of sialylated glycans on glycoproteins, but also that of gangliosides in various tissues and organs.

缺氧在各种疾病的病理生理中大量增加。在该研究项目中，我们专注于缺氧编码细胞粘附分子的基因的诱导机制。我们发现在缺氧条件下明显增强了细胞粘附。缺氧对细胞粘附分子的转录诱导主要由转录因子HIF（低氧诱导因子）介导。由于大多数细胞粘附分子的碳水化合物侧链是由唾液酸残基终止的，因此我们着重于缺氧对唾液酸代谢的影响。唾液酸的细胞量在缺氧下显示出显着增加，这导致了携带唾液酸残基的细胞表面聚糖介导的细胞粘附。这是通过转录诱导的唾液酸转运蛋白的转录诱导，称为sialin。除Sialin外，还可以通过缺氧增强了某些溶糖转移酶的基因转录，包括ST3O。 HIF通过与其他转录因子协作，在某些情况下仅通过HIF的作用来诱导这些基因的转录。人们普遍认为，细胞唾液酸池是通过从头合成唾液酸提供的，但是我们目前的结果表明，通过唾液酸转运蛋白系统掺入唾液酸在供应细胞表面siallated Glycans同步所需的唾液酸残基中也起着重要作用。缺氧诱导的sialin转录不仅影响糖蛋白上的硫化糖的合成，还影响各种组织和器官中的神经节苷脂的合成。