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

缺氧在多种疾病的病理生理学中占有重要地位。本课题主要研究缺氧对细胞粘附分子编码基因的诱导机制。我们发现在缺氧条件下细胞的粘附性明显增强。缺氧对细胞粘附分子基因的转录诱导主要由一种转录因子HIF （hypoxia inducible factor）介导。由于大多数细胞黏附分子具有以唾液酸残基终止的碳水化合物侧链，因此我们重点研究了缺氧对唾液酸代谢的影响。在缺氧条件下，细胞中唾液酸的含量显著增加，这导致携带唾液酸残基的细胞表面聚糖介导的细胞粘附增强。这是由于唾液酸转运体Sialin基因的转录诱导。除Sialin外，一些唾液基转移酶（包括st30）基因的转录也因缺氧而增强。在某些情况下，HIF通过与其他转录因子的合作诱导这些基因的转录，在其他一些情况下，仅通过HIF的作用。人们普遍认为细胞唾液酸库是由唾液酸的从头合成提供的，但我们目前的研究结果表明，通过唾液酸转运系统的唾液酸结合在提供合成细胞表面唾液化聚糖所需的唾液酸残基方面也起着重要作用。缺氧诱导的Sialin转录不仅影响糖蛋白上唾液化聚糖的合成，还影响各组织和器官中神经节苷的合成。

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.