Dual regulation of macrophage migration inhibitory factor (MIF) expression in hypoxia by CREB and HIF-1.
Macrophage migration inhibitory factor (MIF) is a well-described pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. However, despite the compelling evidence that MIF is overexpressed in, and contributes to, the pathology of inflammatory and malignant diseases the mechanisms that contribute to exaggerated expression of MIF have been poorly described. Here we show that hypoxia, and specifically HIF-1alpha, is a potent and rapid inducer of MIF expression. In addition, we demonstrate that hypoxia-induced MIF expression is dependent upon a HRE in the 5'UTR of the MIF gene but is further modulated by CREB expression. We propose a model where hypoxia-induced MIF expression is driven by HIF-1 but amplified by hypoxia-induced degradation of CREB. Given the importance of MIF in inflammatory and malignant diseases these data reveal a HIF-1-mediated pathway as a potential therapeutic target for suppression of MIF expression in hypoxic tissues.
Baugh
John A
JA
School of Medicine and Medical Science, The Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. john.baugh@ucd.ie
Gantier
Michael
M
Li
Lili
L
Byrne
Aileen
A
Buckley
Avril
A
Donnelly
Seamas C
SC
D020121:5' Untranslated Regions / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis*
D020121:5' Untranslated Regions; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008263:Macrophage Migration-Inhibitory Factors