title: Macrophage migration inhibitory factor activates hypoxia-inducible factor in a p53-dependent manner.
abstract: BACKGROUND
  Macrophage migration inhibitory factor (MIF) is not only a cytokine which has a critical role in several inflammatory conditions but also has endocrine and enzymatic functions. MIF is identified as an intracellular signaling molecule and is implicated in the process of tumor progression, and also strongly enhances neovascularization. Overexpression of MIF has been observed in tumors from various organs. MIF is one of the genes induced by hypoxia in an hypoxia-inducible factor 1 (HIF-1)-dependent manner.
  
  
  RESULTS
  The effect of MIF on HIF-1 activity was investigated in human breast cancer MCF-7 and MDA-MB-231 cells, and osteosarcoma Saos-2 cells. We demonstrate that intracellular overexpression or extracellular administration of MIF enhances activation of HIF-1 under hypoxic conditions in MCF-7 cells. Mutagenesis analysis of MIF and knockdown of 53 demonstrates that the activation is not dependent on redox activity of MIF but on wild-type p53. We also indicate that the MIF receptor CD74 is involved in HIF-1 activation by MIF at least when MIF is administrated extracellularly.
  
  
  CONCLUSIONS
  MIF regulates HIF-1 activity in a p53-dependent manner. In addition to MIF's potent effects on the immune system, MIF is linked to fundamental processes conferring cell proliferation, cell survival, angiogenesis, and tumor invasiveness. This functional interdependence between MIF and HIF-1alpha protein stabilization and transactivation activity provide a molecular mechanism for promotion of tumorigenesis by MIF.
authors.affiliation: Department of Anesthesia, Kyoto University Hospital, Kyoto University, Kyoto, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Oda
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Oda
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Nishi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takabuchi
authors.forename: Takuhiko
authors.initials: T
authors.lastname: Wakamatsu
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Tanaka
authors.forename: Takehiko
authors.initials: T
authors.lastname: Adachi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Fukuda
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Kiichi
authors.initials: K
authors.lastname: Hirota
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008263:Macrophage Migration-Inhibitory Factors / Q000502:physiology*; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008263:Macrophage Migration-Inhibitory Factors; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53