A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake
A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake
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DOI：
10.1016/j.cell.2005.10.027
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发表时间：
2005-12-29
期刊：
影响因子：
64.5
通讯作者：
Green, MR
中科院分区：
文献类型：
--
作者：
Devireddy, LR;Gazin, C;Green, MR
脂质运载蛋白小鼠24 p3已经涉及多种生理过程，包括由于白细胞介素-3（IL-3）剥夺和铁转运引起的细胞凋亡。在这里，我们报告24 p3细胞表面受体（24 p3 R）的克隆。异位24 p3 R表达赋予细胞进行铁摄取或凋亡的能力，这取决于配体的铁含量：铁负载的24 p3增加细胞内铁浓度而不促进凋亡;铁缺乏的24 p3降低细胞内铁水平，这诱导促凋亡蛋白Bim的表达，导致凋亡。细胞内铁传递阻断Bim诱导并抑制由于24 p3添加或IL-3剥夺引起的细胞凋亡。我们意外地发现，BCR-ABL癌蛋白激活24 p3的表达并抑制24 p3 R的表达，使BCR-ABL（+）细胞对分泌的24 p3不敏感。通过抑制BCR-ABL，伊马替尼诱导24 p3 R表达，从而诱导细胞凋亡。我们的研究结果揭示了细胞内铁调节在与BCR-ABL诱导的骨髓增生性疾病及其治疗相关的凋亡途径中的意想不到的作用。
The lipocalin mouse 24p3 has been implicated in diverse physiological processes, including apoptosis due to interleukin-3 (IL-3) deprivation and iron transport. Here we report cloning of the 24p3 cell-surface receptor (24p3R). Ectopic 24p3R expression confers on cells the ability to undergo either iron uptake or apoptosis, dependent upon the iron content of the ligand: Iron-loaded 24p3 increases intracellular iron concentration without promoting apoptosis; iron-lacking 24p3 decreases intracellular iron levels, which induces expression of the proapoptotic protein Bim, resulting in apoptosis. Intracellular iron delivery blocks Bim induction and suppresses apoptosis due to 24p3 addition or IL-3 deprivation. We find, unexpectedly, that the BCR-ABL oncoprotein activates expression of 24p3 and represses 24p3R expression, rendering BCR-ABL(+) cells refractory to secreted 24p3. By inhibiting BCR-ABL, imatinib induces 24p3R expression and, consequently, apoptosis. Our results reveal an unanticipated role for intracellular iron regulation in an apoptotic pathway relevant to BCR-ABL-induced myeloproliferative disease and its treatment.