hnRNP A1 nucleocytoplasmic shuttling activity is required for normal myelopoiesis and BCR/ABL leukemogenesis
hnRNP A1 nucleocytoplasmic shuttling activity is required for normal myelopoiesis and BCR/ABL leukemogenesis
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DOI：
10.1128/mcb.22.7.2255-2266.2002
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发表时间：
2002-04-01
影响因子：
5.3
通讯作者：
Perrotti, D
中科院分区：
文献类型：
--
作者：
Iervolino, A;Santilli, G;Perrotti, D
hnRNP A1是一种核胞质穿梭异质核核糖核蛋白，伴随真核mrna从转录活性位点到翻译活性位点。尽管hnRNP A1作为核前mRNA和mRNA加工和输出的调节因子的重要性已得到证实，但尚不清楚这是否与正常细胞和转化细胞的增殖、存活和分化的控制有关。我们在这里表明，hnRNP A1水平在表达p210（BCR/ABL）癌蛋白的髓系祖细胞中，在慢性髓系白血病（CML）原细胞危重患者的单核细胞中以及在疾病进展过程中升高。此外，在髓系祖细胞32Dc13中，BCR/ABL通过阻止其泛素/蛋白酶体依赖性降解来稳定hnRNP A1。为了评估hnRNP A1核细胞质穿梭活性在正常和白血病骨髓形成中的潜在作用，在亲代和BCR/ abl转化的骨髓前体32Dc13细胞、正常小鼠骨髓细胞和CML患者加速期的单个核细胞中异位表达了核输出缺陷突变体。在正常细胞中，该突变体的表达增强了白细胞介素-3剥夺诱导的细胞凋亡的易感性，抑制了粒细胞分化，并诱导粒细胞集落刺激因子处理培养物的大量细胞死亡。在转化的BCR/ABL细胞中，其表达与抑制集落形成和降低体内致瘤潜能有关。此外，干扰hnRNP A1穿梭活性导致C/EBPalpha（粒细胞分化的主要调节因子）和Bcl-X-L（造血细胞的重要存活因子）的下调。总之，这些结果表明，hnRNP A1的穿梭活性对于mrna的核质运输是重要的，这些mrna编码的蛋白质影响正常和BCR/ abl转化的骨髓祖细胞的表型。
hnRNP A1 is a nucleocytoplasmic shuttling heterogeneous nuclear ribonucleoprotein that accompanies eukaryotic mRNAs from the active site of transcription to that of translation. Although the importance of hnRNP A1 as a regulator of nuclear pre-mRNA and mRNA processing and export is well established, it is unknown whether this is relevant for the control of proliferation, survival, and differentiation of normal and transformed cells. We show here that hnRNP A1 levels are increased in myeloid progenitor cells expressing the p210(BCR/ABL) oncoprotein, in mononuclear cells from chronic myelogenous leukemia (CML) blast crisis patients, and during disease progression. In addition, in myeloid progenitor 32Dc13 cells, BCR/ABL stabilizes hnRNP A1 by preventing its ubiquitin/proteasome-dependent degradation. To assess the potential role of hnRNP A1 nucleocytoplasmic shuttling activity in normal and leukemic myelopoiesis, a mutant defective in nuclear export was ectopically expressed in parental and BCR/ABL-transformed myeloid precursor 32Dc13 cells, in normal murine marrow cells, and in mononuclear cells from a CML patient in accelerated phase. In normal cells, expression of this mutant enhanced the susceptibility to apoptosis induced by interleukin-3 deprivation, suppressed granulocytic differentiation, and induced massive cell death of granulocyte colony-stimulating factor-treated cultures. In BCR/ABL,transformed cells, its expression was associated with suppression of colony formation and reduced tumorigenic potential in vivo. Moreover, interference with hnRNP A1 shuttling activity resulted in downmodulation of C/EBPalpha, the major regulator of granulocytic differentiation, and Bcl-X-L, an important survival factor for hematopoietic cells. Together, these results suggest that the shuttling activity of hnRNP A1 is important for the nucleocytoplasmic trafficking of mRNAs that encode proteins influencing the phenotype of normal and BCR/ABL-transformed myeloid progenitors.