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

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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.