第667回　千葉県がんセンター研究局集談会のお知らせ

演題： プロリン水酸化酵素による生体内における低酸素への反応の制御
Regulation of mammalian hypoxic response in vivo by PHD prolyl-hydroxilases

演者： 南嶋　洋司 博士
(Dana-Farber Cancer Institute, Harvard Medical School)

日時： 平成21年2月24日（火曜日） 午後5時～午後6時

場所： 千葉県がんセンター 研究局カンファレンスルーム

要旨： Hypoxia inducible factor (HIF), consisting of a labile alpha subunit and a stable beta subunit, is a master regulator of hypoxia-responsive mRNAs. HIFα undergoes oxygen-dependent prolyl hydroxylation, which marks it for polyubiquitination by a complex containing the von Hippel-Lindau protein (pVHL). PHD2 among the three PHD family members appears to be primary HIF prolyl hydroxylase. Here we report that loss of Phd3 exacerbates the HIF activation, hepatic steatosis, dilated cardiomyopathy, and premature mortality observed in mice lacking Phd2 alone and more closely phenocopies the changes seen in mice lacking pVHL. Importantly, the degree to which Phd3 can compensate for Phd2 loss, and the degree to which combined loss of Phd2 and Phd3 resembles pVHL loss, appears to differ for different HIF-responsive genes and in different tissues. These findings highlight that the response of different HIF target genes to changes in prolyl hydroxylase activity differ, quantitatively and qualitatively, in vivo and have implications for the development of paralog-specific PHD inhibitors as therapeutic agents.