The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme
The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme
复制标题
DOI：
10.1074/jbc.m313599200
复制
发表时间：
2004-06-04
影响因子：
4.8
通讯作者：
Schuetz, JD
中科院分区：
文献类型：
--
作者：
Krishnamurthy, P;Ross, DD;Schuetz, JD
我们的研究表明，ABC转运蛋白和干细胞和祖细胞的标记物，即乳腺癌耐药蛋白（BCRP或ABCG 2），在缺氧条件下具有很强的生存优势。我们发现，在缺氧条件下，与来自Bcrp（+/+）小鼠的祖细胞相比，来自Bcrp（-/-）小鼠的祖细胞形成集落的能力降低。阻断BCRP（+/+）祖细胞中的BCRP功能显著降低缺氧条件下的存活率。然而，阻断血红素生物合成逆转了Bcrp（-/-）祖细胞的缺氧易感性，这一发现表明血红素分子（即卟啉）在缺氧下对Bcrp（-/-）细胞是有害的。BCRP特异性结合血红素，缺乏BCRP的细胞积累卟啉。最后，Bcrp表达上调缺氧，我们证明，这种上调涉及缺氧诱导转录因子复合物HIF-1。总的来说，我们的研究结果表明，细胞可以在缺氧需求时使用BCRP来减少血红素或卟啉的积累，这可能对细胞有害。我们的研究结果对干细胞和肿瘤细胞在缺氧环境中的存活有影响。
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.