Abstract

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent stem cells with ability to self-replicate and differentiate into mesodermal derivatives, such as adipocytes and osteoblasts. BM-MSCs are a critical component of the tumour microenvironment. They support tumour progression by recruiting additional BM-MSCs and by differentiating into myofibroblasts (also called cancer-associated fibroblasts). Protein phosphatase 2A (PP2A) is an essential serine/threonine protein phosphatase that regulates a broad range of cellular signalling. PP2A forms a heterotrimer to dephosphorylate specific substrates. The reversible methylesterification (methylation) of Leu309 in the catalytic subunit of PP2A (PP2Ac) regulates biogenesis of the PP2A holoenzyme. It is unknown whether the methylation of PP2Ac plays a role in BM-MSC differentiation. Our experiments determined that protein levels of PP2A subunits and PP2A methyltransferase (LCMT-1) are significantly altered during differentiation. PP2Ac methylation levels in BM-MSCs decrease over time in response to an adipogenic differentiation stimulus. However, blockage of PP2A demethylation using the PP2A dimethyl-esterase inhibitors enhanced adipocyte differentiation. This suggests that PP2Ac demethylation is involved in adipocyte differentiation resistance. The results of our study provide a greater understanding of the regulation of BM-MSCs differentiation by PP2A holoenzyme.

中文翻译：

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PP2A甲基化参与骨髓源间充质干细胞成脂分化的研究。

摘要

骨髓源间充质干细胞（BM-MSC）是多能干细胞，具有自我复制和分化为中胚层衍生物的能力，例如脂肪细胞和成骨细胞。BM-MSC是肿瘤微环境的关键组成部分。它们通过募集额外的BM-MSC并分化为成肌纤维细胞（也称为癌症相关成纤维细胞）来支持肿瘤进展。蛋白磷酸酶2A（PP2A）是一种必需的丝氨酸/苏氨酸蛋白磷酸酶，可调节广泛的细胞信号传导。PP2A形成异三聚体以使特定底物脱磷酸。PP2A催化亚基（PP2Ac）中Leu309的可逆甲基酯化（甲基化）调节PP2A全酶的生物发生。尚不清楚PP2Ac的甲基化是否在BM-MSC分化中起作用。我们的实验确定了PP2A亚基和PP2A甲基转移酶（LCMT-1）的蛋白质水平在分化过程中发生了显着变化。BM-MSC中的PP2Ac甲基化水平会随着时间的流逝而降低，这是对脂肪形成分化刺激的响应。但是，使用PP2A二甲基酯酶抑制剂阻止PP2A去甲基化可增强脂肪细胞分化。这表明PP2Ac去甲基化与脂肪细胞分化抗性有关。我们的研究结果为PP2A全酶对BM-MSCs分化的调控提供了更深入的了解。使用PP2A二甲基酯酶抑制剂阻止PP2A去甲基化可增强脂肪细胞分化。这表明PP2Ac去甲基化与脂肪细胞分化抗性有关。我们的研究结果为PP2A全酶对BM-MSCs分化的调控提供了更深入的了解。使用PP2A二甲基酯酶抑制剂阻止PP2A去甲基化可增强脂肪细胞分化。这表明PP2Ac去甲基化与脂肪细胞分化抗性有关。我们的研究结果为PP2A全酶对BM-MSCs分化的调控提供了更深入的了解。