PTH 依赖性的 RANKL mRNA 稳定与 KH 型剪接调控蛋白的磷酸化增加有关。

IF 3.8 3区 医学 Q2 CELL BIOLOGY
Gang-Qing Yao, Meiling Zhu, Karl Insogna
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引用次数: 0

摘要

甲状旁腺激素(PTH)受体激动剂可促进骨形成,但也会增加破骨细胞的生成,部分原因是其可增加核因子卡帕Β配体受体激活剂(RANKL)的表达。除了激活转录外,调节 mRNA 的稳定性是控制 mRNA 丰度的另一个重要分子机制。尽管硫代磷酸(TPL)事先抑制了细胞转录,但 PTH 处理 6 小时后,UAMS-32P 细胞中的 RANKL mRNA 表达量仍增加了 7.4 倍。RANKL mRNA 与 TNF 家族的其他成员一样,在 3' UTR 中含有 AU-Rich 元素(AREs)。AU-Rich Element 结合蛋白(ABPs,包括 KSRP、TTP、AUF1 和 HuR)与 AREs 结合并调节 mRNA 的稳定性。与 RANKL mRNA 结合的 KSRP 明显多于其他 ABPs。PTH 并未增加与 RANKL 转录本结合的 ABPs 数量。然而,与先用 TPL 再用 PTH 处理的 UAMS-32P 细胞相比,先用 TPL 再用 PTH 处理的 UAMS-32P 细胞中细胞磷酸化的 KSRP 水平显著增加。细胞 AUF1、HuR 和 TTP 的磷酸化程度在 PTH 处理后没有增加。PTH处理后,细胞中总Pin1和磷酸化Pin1蛋白的含量没有明显变化。我们的结论是,PTH 处理后细胞磷酸-KSRP 的增加,以及与 RANKL mRNA 结合的 KSRP 总量在 PTH 处理后没有变化这一事实,可能表明磷酸-KSRP 在稳定 RANKL 转录本方面发挥了一定的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
PTH-dependent stabilization of RANKL mRNA is associated with increased phosphorylation of the KH-type splicing regulatory protein
Parathyroid hormone (PTH) receptor agonists promote bone formation but also increase osteoclastogenesis, in part by increasing expression of the receptor activator of nuclear factor kappa-Β ligand (RANKL). In addition to activation of transcription, regulation of mRNA stability is another important molecular mechanism controlling mRNA abundance. PTH treatment for 6 h resulted in a 7.4-fold elevation in RANKL mRNA expression in UAMS-32P cells, despite prior inhibition of cellular transcription by thiophosphoryl (TPL). RANKL mRNA, like other TNF family members, contains AU-Rich Elements (AREs) in the 3’ UTR. AU-Rich Element Binding Proteins (ABPs including KSRP, TTP, AUF1 and HuR) bind to AREs and regulate mRNA stability. There was significantly more KSRP bound to RANKL mRNA than any of the other ABPs. PTH did not increase the amount of ABPs bound to the RANKL transcript. However, the level of cellular phosphorylated KSRP was significantly increased in UAMS-32P cells pre-treated with TPL followed by PTH exposure, compared to cells treated with vehicle following TPL. The extent of phosphorylation of cellular AUF1, HuR, and TTP did not increase with PTH treatment. There were no significant changes in the cellular content of total Pin1 and phospho-Pin1 protein with PTH treatment. We conclude that increases in cellular phospho-KSRP following PTH treatment, together with fact that the total amount of the KSRP bound to the RANKL mRNA did not change with PTH-treatment, may indicate that phospho-KSRP plays some role in stabilizing the RANKL transcript.
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来源期刊
Molecular and Cellular Endocrinology
Molecular and Cellular Endocrinology 医学-内分泌学与代谢
CiteScore
9.00
自引率
2.40%
发文量
174
审稿时长
42 days
期刊介绍: Molecular and Cellular Endocrinology was established in 1974 to meet the demand for integrated publication on all aspects related to the genetic and biochemical effects, synthesis and secretions of extracellular signals (hormones, neurotransmitters, etc.) and to the understanding of cellular regulatory mechanisms involved in hormonal control.
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