Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis.
Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis.
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我们发现造血细胞特异性林恩底物1（HCLS 1或HS 1）在人骨髓细胞中高度表达，并且用粒细胞集落刺激因子（G-CSF）刺激导致HCLS 1磷酸化。HCLS 1结合转录因子淋巴样增强子结合因子1（LEF-1），在G-CSF刺激时将LEF-1转运到细胞核中并诱导LEF-1自身调节。在患有严重先天性中性粒细胞减少症的患者中，编码HCLS1相关蛋白X-1（HAX1）的基因中的遗传突变导致G-CSF触发的HCLS1磷酸化的严重缺陷，随后导致LEF-1的自身调节和表达降低。与这些结果一致，HCLS1缺陷型小鼠是血小板减少的。在大多数接受检测的急性髓性白血病患者的骨髓活检中，HCLS 1蛋白表达显著升高，与高水平的G-CSF合成相关，在某些个体中，HCLS 1蛋白富含脯氨酸的区域中的四个残基插入已知加速细胞内信号传导。这些数据证明了HCLS 1在体外和体内骨髓生成中的重要性。
We found that hematopoietic cell–specific Lyn substrate 1 (HCLS1 or HS1) is highly expressed in human myeloid cells and that stimulation with granulocyte colony-stimulating factor (G-CSF) leads to HCLS1 phosphorylation. HCLS1 binds the transcription factor lymphoid-enhancer binding factor 1 (LEF-1), transporting LEF-1 into the nucleus upon G-CSF stimulation and inducing LEF-1 autoregulation. In patients with severe congenital neutropenia, inherited mutations in the gene encoding HCLS1-associated protein X-1 (HAX1) lead to profound defects in G-CSF–triggered phosphorylation of HCLS1 and subsequently to reduced autoregulation and expression of LEF-1. Consistent with these results, HCLS1-deficient mice are neutropenic. In bone marrow biopsies of the majority of tested patients with acute myeloid leukemia, HCLS1 protein expression is substantially elevated, associated with high levels of G-CSF synthesis and, in some individuals, a four-residue insertion in a proline-rich region of HCLS1 protein known to accelerate intracellular signaling. These data demonstrate the importance of HCLS1 in myelopoiesis in vitro and in vivo.
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