Macrophage migration inhibitory factor manipulation and evaluation in tumoral hypoxic adaptation.

Increasingly clear is an important regulatory role for hypoxia-inducible factor 1alpha (HIF-1alpha) in the expression of the cytokine/growth factor macrophage migration inhibitory factor (MIF). The functional significance of hypoxia-induced MIF expression is revealed by findings demonstrating that HIF-1alpha-dependent MIF expression is necessary for hypoxia-induced evasion from cell senescence and that MIF is necessary for HIF-1alpha stabilization induced by hypoxia and prolyl hydroxylase (PHD) inhibitors. Both of these activities attributed to MIF likely involve the modulation of protein degratory pathways mediated by cullin-dependent E3 ubiquitin ligase complexes and their regulation by the COP9 signalosome (CSN). As the importance of MIF in hypoxic adaptation of human tumors is now becoming fully realized, we review protocols designed to evaluate MIF expression, activity, and functional consequences in hypoxic environments.