Devireddy Laxminarayana R, Gazin Claude, Zhu Xiaochun, Green Michael R
Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cell. 2005 Dec 29;123(7):1293-305. doi: 10.1016/j.cell.2005.10.027.
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.
脂质运载蛋白小鼠24p3参与了多种生理过程，包括因白细胞介素-3（IL-3）缺乏引起的细胞凋亡和铁转运。在此，我们报告了24p3细胞表面受体（24p3R）的克隆。异位表达24p3R赋予细胞摄取铁或发生凋亡的能力，这取决于配体的铁含量：载铁的24p3可增加细胞内铁浓度而不促进细胞凋亡；缺铁的24p3可降低细胞内铁水平，从而诱导促凋亡蛋白Bim的表达，导致细胞凋亡。细胞内铁传递可阻断Bim的诱导，并抑制因添加24p3或缺乏IL-3而引起的细胞凋亡。我们意外地发现，BCR-ABL癌蛋白可激活24p3的表达并抑制24p3R的表达，使BCR-ABL(+)细胞对分泌的24p3产生抗性。通过抑制BCR-ABL，伊马替尼可诱导24p3R的表达，从而导致细胞凋亡。我们的结果揭示了细胞内铁调节在与BCR-ABL诱导的骨髓增殖性疾病及其治疗相关的凋亡途径中的意外作用。
