Deprivation of oxygen causes metabolic adaptations within a cell to facilitate survival. One adaptation to altered oxygen levels is a change in cellular heme. We have recently demonstrated that ABCB6 is localized to the mitochondria and regulates cellular heme levels. The major transcriptional sensor of oxygen is hypoxia-inducible factor (HIF). We investigated whether HIF is involved in the transcriptional activation of ABCB6 and the functional significance of this activation to cells under hypoxic conditions. We found that ABCB6 expression is increased by hypoxia in several cell types. Further, ABCB6 promoter contains hypoxia response (HRE) elements. These HREs are functional because the promoter is activated by the hypoxia mimetic, desferoxamine as well as directly by co-transfected HIF1-alpha. Moreover, in cells with a defective HIF, ABCB6 expression is not upregulated by hypoxia. Finally, ectopic overexpression of ABCB6 reveals that ABCB6 protects cells from the cytotoxicity induced by hypoxia. These studies reveal that ABCB6, a regulator of cytosolic heme levels, is regulated by hypoxia and the major hypoxia transcription factor HIF1-alpha. This upregulation by hypoxia is compatible with ABCB6 overexpression providing a survival advantage under hypoxic conditions, this is relevant because ABCB6 is overexpressed in solid tumors.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]