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Biomedical subjects

A Tokura

Publications and source records attributed to A Tokura.

4 recordsLinked to original sources
PubMed2000

Regulation of macrophage-specific gene expression by degenerated lipoproteins.

The effect of aggregated low-density lipoprotein (agLDL) on cell viability and macrophage-specific gene expression using human peripheral blood monocytes in culture was investigated. AgLDL suppressed activation-induced cell death of phorbol ester-treated macrophages. The inhibition of apoptosis was accompanied by downregulation of apoptosis-promoting proteases, including interleukin-1beta-converting enzyme (ICE) and CPP32 and upregulation of anti-apoptotic cytokine (interleukin-1beta (IL-1beta)). In contrast, macrophage-colony stimulating factor (M-CSF) enhanced cell death of lipid-bearing macrophages, suggesting that the anti-atherogenic action of M-CSF is at least in part mediated through apoptotic elimination of macrophages. Then, we attempted to isolate the genes specifically induced by agLDL in macrophages using a subtraction-based cloning strategy. One of the genes isolated, termed LIG (LDL-inducible gene), encodes a human homolog of E2 ubiquitin-conjugating enzyme. Ubiquitination of multiple intracellular proteins was observed in agLDL-treated macrophages, which coincided with upregulation of LIG. These results suggest that LIG acts as a direct mediator of foam cell formation through polyubiquitination and subsequent degradation of cellular proteins with apoptosis-inducing properties. The regulation of apoptosis by macrophage-specific gene expression may contribute to foam cell formation and atherosclerosis.

Apoptosis↗
PubMed2000

Induction of ubiquitin-conjugating enzyme by aggregated low density lipoprotein in human macrophages and its implications for atherosclerosis.

Recently, we have found that aggregated low density lipoprotein (agLDL) inhibits apoptosis of lipid-bearing macrophages, thereby facilitating foam cell formation and atherosclerosis. To clarify the mechanisms by which agLDL inhibits apoptosis of macrophages, we isolated the genes specifically induced by agLDL by using a subtraction-based cloning strategy. One of the cloned genes, termed low density lipoprotein (LDL)-inducible gene (LIG), encodes a human homologue of bovine ubiquitin-conjugating enzyme E2-25K. Although LIG mRNA was ubiquitously expressed among human tissues, including hematopoietic cells, the abundance of transcripts was markedly increased by agLDL treatment in activated monocytes. LIG mRNA expression was not enhanced by nonatherogenic lipoproteins such as native LDL and high density lipoprotein, suggesting a role in atherosclerosis. Polyubiquitination of intracellular proteins was observed in monocytes cultured with agLDL, which coincided with upregulation of LIG. Furthermore, ubiquitin-dependent degradation of p53, an inducer of apoptosis, was accompanied by LIG induction in agLDL-treated monocytes. The antiapoptotic effect of agLDL was abrogated by a specific proteasome inhibitor, which also increased the half-life of p53 in monocytes. These results suggest that LIG contributes to foam cell formation by the suppression of apoptosis of lipid-bearing macrophages through ubiquitination and subsequent degradation of p53.

Amino Acid Sequence↗