HIF1α delays premature senescence through the activation of MIF
HIF1α delays premature senescence through the activation of MIF
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DOI：
10.1101/gad.1471106
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发表时间：
2006-12-15
影响因子：
10.5
通讯作者：
Giaccia, Amato J.
中科院分区：
文献类型：
--
作者：
Welford, Scott M.;Bedogni, Barbara;Giaccia, Amato J.
体外过早衰老归因于氧化应激导致DNA损伤反应。在没有发生在大气氧水平的氧化损伤的情况下，未转化细胞的增殖持续了很长一段时间。我们研究了缺氧诱导因子1 α (HIF1 α)转录因子在有氧和缺氧条件下预防衰老的作用。利用条件HIF1 α敲除小鼠的胚胎成纤维细胞，我们发现有氧条件下HIF1 α的缺失显著加速了细胞衰老的发生，并减少了缺氧条件下的增殖。此外，我们发现巨噬细胞迁移抑制因子（MIF）是HIF1 α延缓衰老的关键效应因子。抑制MIF表型导致HIF1 α缺失。我们的研究结果强调了HIF1 α在有氧条件下的新作用，并确定MIF是负责这一功能的靶标。
Premature senescence in vitro has been attributed to oxidative stress leading to a DNA damage response. In the absence of oxidative damage that occurs at atmospheric oxygen levels, proliferation of untransformed cells continues for extended periods of time. We have investigated the role of the hypoxia-inducible factor 1 alpha (HIF1 alpha) transcription factor in preventing senescence in aerobic and hypoxic conditions. Using embryonic fibroblasts from a conditional HIF1 alpha knockout mouse, we found that loss of HIF1 alpha under aerobic conditions significantly accelerated the onset of cellular senescence, and decreased proliferation under hypoxia. Furthermore, we identify the macrophage migration inhibitory factor (MIF) as a crucial effector of HIF1 alpha that delays senescence. Inhibition of MIF phenocopies loss of HIF1 alpha. Our findings highlight a novel role for HIF1 alpha under aerobic conditions, and identify MIF as a target responsible for this function.