Abstract
BackgroundMacrophage 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.Methods/Principal FindingsThe 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.Conclusion/SignificanceMIF 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-1α protein stabilization and transactivation activity provide a molecular mechanism for promotion of tumorigenesis by MIF.
Highlights
Macrophage migration inhibitory factor (MIF) was originally described as a T cell–derived lymphokine but is recognized as a pluripotent cytokine involved in multiple functions within and beyond the immune system [1]
We demonstrate that intracellular overexpression or extracellular administration of MIF enhances activation of hypoxia-inducible factor 1 (HIF-1) under hypoxic conditions and that the regulation is not dependent on redox activity of MIF but on wild-type p53
Because MIF is a cellular factor released from cells, we investigated the impact of recombinant human MIF protein on MCF-7 cells. rhMIF increased HIF-1a expression in a dose-dependent manner under hypoxic conditions whereas HIF1b expression was not affected (Fig. 1D). rhMIF treatment augmented HIF-1a protein levels in cells treated with iron chelator DFX which inhibits HIF-1a-hydroxylase activity
Summary
Macrophage migration inhibitory factor (MIF) was originally described as a T cell–derived lymphokine but is recognized as a pluripotent cytokine involved in multiple functions within and beyond the immune system [1]. Increased MIF mRNA expression has been reported in metastatic prostate cancer and ductal breast carcinoma. Following these findings, it became evident that MIF is involved in the development of lymphoma and tumor-associated angiogenesis [3,4]. Macrophage migration inhibitory factor (MIF) is a cytokine which has a critical role in several inflammatory conditions and has endocrine and enzymatic functions. MIF is one of the genes induced by hypoxia in an hypoxia-inducible factor 1 (HIF-1)-dependent manner
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
