The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme

Partha Krishnamurthy, Douglas D. Ross, Takeo Nakanishi, Kim Bailey-Dell, Sheng Zhou, Kelly E. Mercer, B. Sarkadi, Brian P. Sorrentino, John D. Schuetz

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)24218-24225
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number23
DOIs
Publication statusPublished - Jun 4 2004

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Stem cells
Heme
Cell Survival
Porphyrins
Stem Cells
Cells
ATP-Binding Cassette Transporters
Biosynthesis
Tumors
Cell Hypoxia
Transcription Factors
Neoplastic Stem Cells
Molecules
Up-Regulation
Breast Neoplasms
Proteins
Hypoxia

ASJC Scopus subject areas

  • Biochemistry

Cite this

Krishnamurthy, P., Ross, D. D., Nakanishi, T., Bailey-Dell, K., Zhou, S., Mercer, K. E., ... Schuetz, J. D. (2004). The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. Journal of Biological Chemistry, 279(23), 24218-24225. https://doi.org/10.1074/jbc.M313599200

The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. / Krishnamurthy, Partha; Ross, Douglas D.; Nakanishi, Takeo; Bailey-Dell, Kim; Zhou, Sheng; Mercer, Kelly E.; Sarkadi, B.; Sorrentino, Brian P.; Schuetz, John D.

In: Journal of Biological Chemistry, Vol. 279, No. 23, 04.06.2004, p. 24218-24225.

Research output: Contribution to journalArticle

Krishnamurthy, P, Ross, DD, Nakanishi, T, Bailey-Dell, K, Zhou, S, Mercer, KE, Sarkadi, B, Sorrentino, BP & Schuetz, JD 2004, 'The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme', Journal of Biological Chemistry, vol. 279, no. 23, pp. 24218-24225. https://doi.org/10.1074/jbc.M313599200
Krishnamurthy P, Ross DD, Nakanishi T, Bailey-Dell K, Zhou S, Mercer KE et al. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. Journal of Biological Chemistry. 2004 Jun 4;279(23):24218-24225. https://doi.org/10.1074/jbc.M313599200
Krishnamurthy, Partha ; Ross, Douglas D. ; Nakanishi, Takeo ; Bailey-Dell, Kim ; Zhou, Sheng ; Mercer, Kelly E. ; Sarkadi, B. ; Sorrentino, Brian P. ; Schuetz, John D. / The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 23. pp. 24218-24225.
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