RSK-mediated nuclear accumulation of the cold-shock Y-box protein-1 controls proliferation of T cells and T-ALL blasts
RSK-mediated nuclear accumulation of the cold-shock Y-box protein-1 controls proliferation of T cells and T-ALL blasts
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DOI：
10.1038/cdd.2016.141
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发表时间：
2017-02-01
影响因子：
12.4
通讯作者：
Brunner-Weinzierl, Monika C.
中科院分区：
文献类型：
--
作者：
Gieseler-Halbach, Steffi;Meltendorf, Stefan;Brunner-Weinzierl, Monika C.
增殖失调是肿瘤进展的关键。尽管实体瘤细胞的不受限制的增殖与细胞核中的冷休克蛋白Y-box（YB）结合蛋白-1积累相关，但对其在造血系统恶性肿瘤（如T细胞急性淋巴细胞白血病（T-ALL））中的表达和功能知之甚少。在这里，我们表明，YB-1蛋白是高度富集在活化的T细胞和恶性人类T-ALL细胞系的细胞核，但不是在静息T细胞。模拟（S102 D）或阻止磷酸化（S102 N）的YB-1 S-102突变分别导致YB-1在T细胞核中的积累或严格排除它。核糖体S6激酶（RSK）的失活足以消除T细胞和T-ALL细胞增殖，表明RSK介导细胞周期进程，可能依赖于YB-1磷酸化。事实上，磷酸化模拟YB-1（S102 D）增强增殖，这意味着S-102磷酸化是恶性T细胞增殖的先决条件。在T-ALL的初始诊断中，YB-1定位在来自骨髓或外周血的肿瘤母细胞的细胞核中显著改变。我们的数据显示，细胞核中YB-1的失调是T-ALL母细胞的一个尚未报道的特征，并可能改进限制造血系统肿瘤进展的策略。
Deregulated proliferation is key to tumor progression. Although unrestricted proliferation of solid tumor cells correlates with the cold-shock protein Y-box (YB)-binding protein-1 accumulation in the nuclei, little is known about its expression and function in hematopoietic malignancies, such as T-cell acute lymphoblastic leukemia (T-ALL). Here we show that YB-1 protein is highly enriched in the nuclei of activated T cells and malignant human T-ALL cell lines but not in resting T cells. YB-1 S-102 mutations that either mimic (S102D) or prevent phosphorylation (S102N) led to accumulation of YB-1 in the nucleus of T cells or strictly excluded it, respectively. Inactivation of ribosomal S6 kinase (RSK) was sufficient to abrogate T-cell and T-ALL cell proliferation, suggesting that RSK mediates cell-cycle progression, possibly dependent on YB-1-phosphorylation. Indeed, phosphomimetic YB-1(S102D) enhanced proliferation implying that S-102 phosphorylation is a prerequisite for malignant T-cell proliferation. At initial diagnosis of T-ALL, YB-1 localization was significantly altered in the nuclei of tumor blasts derived from bone marrow or peripheral blood. Our data show deregulated YB-1 in the nucleus as a yet unreported characteristic of T-ALL blasts and may refine strategies to restrict progression of hematopoietic tumors.