Inhibition of protein phosphatase PPM1D enhances retinoic acid-induced differentiation in human embryonic carcinoma cell line
Inhibition of protein phosphatase PPM1D enhances retinoic acid-induced differentiation in human embryonic carcinoma cell line
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抑制蛋白磷酸酶 PPM1D 增强视黄酸诱导的人胚胎癌细胞系分化
DOI：
10.1093/jb/mvy119
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Sakaguchi Kazuyasu
中科院分区：
文献类型：
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作者：
Ogasawara Sari;Chuman Yoshiro;Michiba Takahiro;Kamada Rui;Imagawa Toshiaki;Sakaguchi Kazuyasu
蛋白磷酸酶PPM1D(Wip1)最初被确定为P53的靶产物。PPM1D的激活通过抑制P53和其他DNA损伤反应蛋白，通过不同的机制促进各种癌症的致癌潜能。最近发现了PPM1D在细胞分化等生理过程中的新功能。然而，维持茎干和诱导细胞分化的信号通路的调控机制仍不清楚。在这里，我们报告了PPM1D调制维甲酸(RA)信号。PPM1D基因敲除导致人畸胎癌细胞系NT2/D1碱性磷酸酶活性降低。抑制PPM1D诱导的细胞分化并降低干细胞标记物Oct-4(Pou5f1)的基因表达。通过降低PPM1D活性促进RA诱导的细胞分化。RA诱导MEK-ERK通路的激活，并诱导细胞外信号调节蛋白1/2(ERK-1/2)的快速和瞬时激活。PPM1D体外去磷酸化ERK-1/2中的一个带有Tey基序的磷酸肽。此外，抑制PPM1D可促进ERK-1/2的磷酸化。我们的研究表明，PPM1D在维持未分化状态中起重要作用，并在RA诱导的ERK调节和细胞分化中发挥新的功能。
The protein phosphatase PPM1D (Wip1) was originally identified as a p53 target product. Activation of PPM1D through various mechanism promotes the tumorigenic potential of various cancers by suppressing p53 and other DNA damage response proteins. New functions of PPM1D have recently been revealed in physiological processes such as cell differentiation. However, the regulatory mechanisms of signalling pathway to maintain stemness and induce cell differentiation are still unclear. Here we report that PPM1D modulates retinoic acid (RA) signalling. PPM1D knockdown resulted in decreased alkaline phosphatase activity of the human teratocarcinoma cell line NT2/D1. Inhibition of PPM1D-induced cell differentiation and decreased gene expression of the stem cell marker Oct-4 (POU5F1). RA-induced cell differentiation was promoted by reducing PPM1D activity. RA treatment elicited activation of the MEK-ERK pathway and induced rapid and transient activation of the extracellular signal-regulated kinase 1/2 (ERK-1/2). PPM1D dephosphorylated a phosphopeptide with the TEY motif in ERK-1/2in vitro. Moreover, phosphorylation of ERK-1/2 was facilitated by PPM1D inhibition. Our study shows that PPM1D plays an important role in maintaining the undifferentiation state and a new function in RA-induced ERK regulation and cell differentiation.