Zhou Quansheng, Zhao Ji, Wiedmer Therese, Sims Peter J
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Blood. 2002 Jun 1;99(11):4030-8. doi: 10.1182/blood-2001-12-0271.
Phospholipid scramblase 1 (PLSCR1) is an endofacial plasma membrane protein proposed to participate in transbilayer movement of phosphatidylserine and other phospholipids. In addition to its putative role in the reorganization of plasma membrane phospholipids, PLSCR1 is a substrate of intracellular kinases that imply its possible participation in diverse signaling pathways underlying proliferation, differentiation, or apoptosis. Because PLSCR1 is prominently expressed in a variety of blood cells, we evaluated PLSCR activity in platelets and erythrocytes, and cytokine-dependent growth of hematopoietic precursor cells, of PLSCR1 knock-out mice. Adult PLSCR1(-/-) mice showed no obvious hematologic or hemostatic abnormality, and blood cells from these animals normally mobilized phosphatidylserine to the cell surface upon stimulation. Whereas blood cell counts in adult PLSCR1(-/-) mice were normal, in both fetus and newborn animals neutrophil counts were significantly depressed relative to age-matched wild type (WT). Furthermore, when compared with WT, hematopoietic precursor cells from PLSCR1(-/-) mice showed defective colony formation and impaired differentiation to mature granulocytes as stimulated by stem cell factor and granulocyte colony-stimulating factor (G-CSF). By contrast, PLSCR1(-/-) cells showed normal colony formation stimulated by interleukin-3 or granulocyte-macrophage CSF, and expansion of megakaryocytic and erythroid progenitors by thrombopoietin or erythropoietin was unaffected. Stem cell factor and G-CSF were also found to induce marked increases in PLSCR1 levels in WT cells. Consistent with in vitro assays, PLSCR1(-/-) mice treated with G-CSF showed less than 50% of the granulocytosis observed in identically treated WT mice. These data provide direct evidence that PLSCR1 functionally contributes to cytokine-regulated cell proliferation and differentiation and suggest it is required for normal myelopoiesis.
磷脂翻转酶1（PLSCR1）是一种内膜质膜蛋白，被认为参与磷脂酰丝氨酸和其他磷脂的跨膜运动。除了在质膜磷脂重组中可能发挥的作用外，PLSCR1还是细胞内激酶的底物，这暗示其可能参与增殖、分化或凋亡等多种信号通路。由于PLSCR1在多种血细胞中显著表达，我们评估了PLSCR1基因敲除小鼠的血小板和红细胞中的PLSCR活性，以及造血前体细胞的细胞因子依赖性生长。成年PLSCR1（-/-）小鼠没有明显的血液学或止血异常，这些动物的血细胞在受到刺激时能正常地将磷脂酰丝氨酸转运到细胞表面。虽然成年PLSCR1（-/-）小鼠的血细胞计数正常，但在胎儿和新生动物中，中性粒细胞计数相对于年龄匹配的野生型（WT）显著降低。此外，与WT相比，PLSCR1（-/-）小鼠的造血前体细胞在受到干细胞因子和粒细胞集落刺激因子（G-CSF）刺激时，集落形成存在缺陷，向成熟粒细胞的分化受损。相比之下，PLSCR1（-/-）细胞在受到白细胞介素-3或粒细胞-巨噬细胞集落刺激因子刺激时，集落形成正常，血小板生成素或促红细胞生成素对巨核细胞和红系祖细胞的扩增也没有影响。还发现干细胞因子和G-CSF能诱导WT细胞中PLSCR1水平显著升高。与体外实验结果一致，用G-CSF处理的PLSCR1（-/-）小鼠的粒细胞增多情况不到相同处理的WT小鼠的50%。这些数据提供了直接证据，表明PLSCR1在功能上有助于细胞因子调节的细胞增殖和分化，并表明它是正常骨髓生成所必需的。
