Department of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
J Biol Chem. 2011 Aug 26;286(34):30181-9. doi: 10.1074/jbc.M111.245423. Epub 2011 Jul 6.
Glucocorticoid hormones, including dexamethasone, induce apoptosis in lymphocytes and consequently are used clinically as chemotherapeutic agents in many hematologic malignancies. Dexamethasone also induces autophagy in lymphocytes, although the mechanism is not fully elucidated. Through gene expression analysis, we found that dexamethasone induces the expression of a gene encoding a stress response protein variously referred to as Dig2, RTP801, or REDD1. This protein is reported to inhibit mammalian target of rapamycin (mTOR) signaling. Because autophagy is one outcome of mTOR inhibition, we investigated the hypothesis that Dig2/RTP801/REDD1 elevation contributes to autophagy induction in dexamethasone-treated lymphocytes. In support of this hypothesis, RNAi-mediated suppression of Dig2/RTP801/REDD1 reduces mTOR inhibition and autophagy in glucocorticoid-treated lymphocytes. We observed similar results in Dig2/Rtp801/Redd1 knock-out murine thymocytes treated with dexamethasone. Dig2/RTP801/REDD1 knockdown also leads to increased levels of dexamethasone-induced cell death, suggesting that Dig2/RTP801/REDD1-mediated autophagy promotes cell survival. Collectively, these findings demonstrate for the first time that elevation of Dig2/RTP801/REDD1 contributes to the induction of autophagy.
糖皮质激素，包括地塞米松，诱导淋巴细胞凋亡，因此临床上被用作许多血液恶性肿瘤的化疗药物。地塞米松也诱导淋巴细胞自噬，尽管其机制尚未完全阐明。通过基因表达分析，我们发现地塞米松诱导一种编码应激反应蛋白的基因表达，该蛋白被不同地称为 Dig2、RTP801 或 REDD1。据报道，这种蛋白质抑制哺乳动物雷帕霉素靶蛋白（mTOR）信号。因为自噬是 mTOR 抑制的一种结果，所以我们研究了 Dig2/RTP801/REDD1 升高是否有助于地塞米松处理的淋巴细胞中自噬的诱导。支持这一假说，Dig2/RTP801/REDD1 的 RNAi 介导抑制降低了糖皮质激素处理的淋巴细胞中的 mTOR 抑制和自噬。我们在用地塞米松处理的 Dig2/Rtp801/Redd1 敲除鼠胸腺细胞中观察到类似的结果。Dig2/RTP801/REDD1 敲低也导致地塞米松诱导的细胞死亡水平增加，表明 Dig2/RTP801/REDD1 介导的自噬促进细胞存活。总之，这些发现首次表明 Dig2/RTP801/REDD1 的升高有助于自噬的诱导。
