Arginine methylation of the p30 C/EBPα oncoprotein regulates progenitor proliferation and myeloid differentiation.

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES iScience Pub Date : 2024-10-18 eCollection Date: 2024-11-15 DOI:10.1016/j.isci.2024.111199

Linh T Nguyen, Karin Zimmermann, Elisabeth Kowenz-Leutz, Dorothea Dörr, Anja Schütz, Jörg Schönheit, Alexander Mildner, Achim Leutz

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Abstract

The transcription factor CCAAT enhancer binding protein alpha (C/EBPα) is a master regulator of myelopoiesis. CEBPA encodes a long (p42) and a truncated (p30) protein isoform from a single mRNA. Mutations that abnormally enhance expression of p30 are associated with acute myelogenous leukemia (AML). We show by mutational analysis that three highly conserved arginine residues in the p30 C/EBPα N-terminus, previously found to be methylated, are involved in myeloid lineage commitment, progenitor proliferation, and differentiation. The conservative amino acid substitution with lysine that retains the amino acid side chain charge enhanced progenitor proliferation, while a non-conservative substitution with uncharged side chains (alanine, leucine) impaired proliferation and enhanced granulopoiesis. Analysis of protein interactions suggested that arginine methylation of p30 C/EBPα differentially determines interactions with SWI/SNF and MLL complexes. Pharmacological targeting of p30 C/EBPα arginine methylation may have clinical relevance in myeloproliferative and inflammatory diseases, in neutropenia, and in leukemic stem cells.

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p30 C/EBPα 肿瘤蛋白的精氨酸甲基化调节祖细胞增殖和骨髓分化。

转录因子 CCAAT 增强子结合蛋白α（C/EBPα）是骨髓造血的主要调节因子。CEBPA 通过单个 mRNA 编码一个长蛋白（p42）和一个截短蛋白（p30）异构体。异常增强 p30 表达的突变与急性髓性白血病（AML）有关。我们通过突变分析表明，p30 C/EBPα N-末端的三个高度保守的精氨酸残基参与了髓系的形成、祖细胞的增殖和分化。保守的氨基酸替换为保留氨基酸侧链电荷的赖氨酸可促进祖细胞增殖，而非保守的氨基酸替换为不带电的侧链（丙氨酸、亮氨酸）则会阻碍增殖并促进粒细胞生成。蛋白质相互作用分析表明，p30 C/EBPα 的精氨酸甲基化在不同程度上决定了与 SWI/SNF 和 MLL 复合物的相互作用。以 p30 C/EBPα 精氨酸甲基化为药物靶点可能对骨髓增生性疾病、炎症性疾病、中性粒细胞减少症和白血病干细胞具有临床意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

期刊介绍： Science has many big remaining questions. To address them, we will need to work collaboratively and across disciplines. The goal of iScience is to help fuel that type of interdisciplinary thinking. iScience is a new open-access journal from Cell Press that provides a platform for original research in the life, physical, and earth sciences. The primary criterion for publication in iScience is a significant contribution to a relevant field combined with robust results and underlying methodology. The advances appearing in iScience include both fundamental and applied investigations across this interdisciplinary range of topic areas. To support transparency in scientific investigation, we are happy to consider replication studies and papers that describe negative results. We know you want your work to be published quickly and to be widely visible within your community and beyond. With the strong international reputation of Cell Press behind it, publication in iScience will help your work garner the attention and recognition it merits. Like all Cell Press journals, iScience prioritizes rapid publication. Our editorial team pays special attention to high-quality author service and to efficient, clear-cut decisions based on the information available within the manuscript. iScience taps into the expertise across Cell Press journals and selected partners to inform our editorial decisions and help publish your science in a timely and seamless way.