HIF1α delays premature senescence through the activation of MIF

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.