Genes: Structure and Regulation
The Stem Cell Marker Bcrp/ABCG2 Enhances Hypoxic Cell Survival through Interactions with Heme*

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Our studies demonstrate that the ABC transporter and marker of stem and progenitor cells known as the breast cancer resistance protein (BCRP or ABCG2) confers a strong survival advantage under hypoxic conditions. We show that, under hypoxia, progenitor cells from Bcrp/mice have a reduced ability to form colonies as compared with progenitor cells from Bcrp+/+ mice. Blocking BCRP function in Bcrp+/+ progenitor cells markedly reduces survival under hypoxic conditions. However, blocking heme biosynthesis reverses the hypoxic susceptibility of Bcrp–/– progenitor cells, a finding that indicates that heme molecules (i.e. porphyrins) are detrimental to Bcrp–/– cells under hypoxia. BCRP specifically binds heme, and cells lacking BCRP accumulate porphyrins. Finally, Bcrp expression is up-regulated by hypoxia, and we demonstrate that this up-regulation involves the hypoxia-inducible transcription factor complex HIF-1. Collectively, our findings suggest that cells can, upon hypoxic demand, use BCRP to reduce heme or porphyrin accumulation, which can be detrimental to cells. Our findings have implications for the survival of stem cells and tumor cells in hypoxic environments.

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This work was supported by National Institutes of Health Research Grants CA77545, GM60346, ES058571, HL67366, and P30 CA21745, a Cancer Center support grant, a Department of Veterans Affairs Merit Review grant (to D. D. R.), a grant from the American Lebanese Syrian Associated Charities (ALSAC), Hungarian Research Fund Grant OTKA T-31952, and a Howard Hughes International Scholarship (to B. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains two supplemental figures.