Altered CELF1 binding to target transcripts in malignant T cells.
Altered CELF1 binding to target transcripts in malignant T cells.
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DOI：
10.1261/rna.049940.115
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发表时间：
2015-10
期刊：
影响因子：
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通讯作者：
Vlasova-St Louis IA
中科院分区：
文献类型：
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作者：
Bohjanen PR;Moua ML;Guo L;Taye A;Vlasova-St Louis IA
rna结合蛋白CELF1结合到一个被称为富含谷氨酸的元件（GRE）的调控序列上，并控制调控细胞活化、增殖和凋亡的mRNA转录网络。我们使用抗celf1抗体进行免疫沉淀，随后使用微阵列鉴定共硫化转录本。我们发现，与原代人T细胞相比，在H9和Jurkat恶性T细胞系中，CELF1与一组不同的靶转录物结合。在静止的正常T细胞中，CELF1不被磷酸化，但在恶性T细胞中，CELF1的磷酸化与其无法结合正常T细胞中作为CELF1靶点的含有grea的mrna相关。在恶性T细胞中，CELF1缺乏与这些mrna的结合与这些转录物的稳定和表达增加相关。在t细胞急性淋巴细胞白血病患者的原发肿瘤细胞中，一些编码细胞生长调节因子的含有gr的转录本也被稳定和上调。有趣的是，编码许多细胞增殖抑制因子的转录本在恶性T细胞（而不是正常T细胞）中作为CELF1的靶标，与正常T细胞相比，在恶性T细胞中表现出加速降解和表达减少，这与CELF1介导结合转录本降解的已知功能一致。总体而言，恶性T细胞中的CELF1功能障碍导致含有促进细胞生长的gr转录本的一个亚群上调，以及抑制细胞生长的另一个亚群的下调，从而产生驱动恶性表型的净效应。
The RNA-binding protein, CELF1, binds to a regulatory sequence known as the GU-rich element (GRE) and controls a network of mRNA transcripts that regulate cellular activation, proliferation, and apoptosis. We performed immunoprecipitation using an anti-CELF1 antibody, followed by identification of copurified transcripts using microarrays. We found that CELF1 is bound to a distinct set of target transcripts in the H9 and Jurkat malignant T-cell lines, compared with primary human T cells. CELF1 was not phosphorylated in resting normal T cells, but in malignant T cells, phosphorylation of CELF1 correlated with its inability to bind to GRE-containing mRNAs that served as CELF1 targets in normal T cells. Lack of binding by CELF1 to these mRNAs in malignant T cells correlated with stabilization and increased expression of these transcripts. Several of these GRE-containing transcripts that encode regulators of cell growth were also stabilized and up-regulated in primary tumor cells from patients with T-cell acute lymphoblastic leukemia. Interestingly, transcripts encoding numerous suppressors of cell proliferation that served as targets of CELF1 in malignant T cells, but not normal T cells, exhibited accelerated degradation and reduced expression in malignant compared with normal T cells, consistent with the known function of CELF1 to mediate degradation of bound transcripts. Overall, CELF1 dysfunction in malignant T cells led to the up-regulation of a subset of GRE-containing transcripts that promote cell growth and down-regulation of another subset that suppress cell growth, producing a net effect that would drive a malignant phenotype.