HIF1α delays premature senescence through the activation of MIF

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Abstract
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 1α (HIF1α) transcription factor in preventing senescence in aerobic and hypoxic conditions. Using embryonic fibroblasts from a conditional HIF1α knockout mouse, we found that loss of HIF1α 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 HIF1α that delays senescence. Inhibition of MIF phenocopies loss of HIF1α. Our findings highlight a novel role for HIF1α under aerobic conditions, and identify MIF as a target responsible for this function.