HIF1alpha 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 1alpha (HIF1alpha) transcription factor in preventing senescence in aerobic and hypoxic conditions. Using embryonic fibroblasts from a conditional HIF1alpha knockout mouse, we found that loss of HIF1alpha 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 HIF1alpha that delays senescence. Inhibition of MIF phenocopies loss of HIF1alpha. Our findings highlight a novel role for HIF1alpha under aerobic conditions, and identify MIF as a target responsible for this function.
Welford
Scott M
SM
Division of Radiation and Cancer Biology, Stanford University, Stanford, California 94305, USA.
Bedogni
Barbara
B
Gradin
Katarina
K
Poellinger
Lorenz
L
Broome Powell
Marianne
M
Giaccia
Amato J
AJ
D000332:Aerobiosis; D000818:Animals; D015687:Cell Hypoxia; D016922:Cellular Senescence / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology* / Q000528:radiation effects; D005720:Gamma Rays; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000502:physiology*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D014158:Transcription, Genetic
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse