Inhibition of protein phosphatase PPM1D enhances retinoic acid-induced differentiation in human embryonic carcinoma cell line
| Autor: | Yoshiro Chuman, Takahiro Michiba, Kazuyasu Sakaguchi, Sari Ogasawara, Toshiaki Imagawa, Rui Kamada |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
MAPK/ERK pathway
Cellular differentiation Phosphatase Retinoic acid Antineoplastic Agents Tretinoin Biochemistry 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Carcinoma Embryonal Cell Line Tumor Humans Molecular Biology Protein Kinase Inhibitors 030304 developmental biology Cell Proliferation Mitogen-Activated Protein Kinase 1 0303 health sciences Mitogen-Activated Protein Kinase 3 Chemistry Kinase 030302 biochemistry & molecular biology Cell Differentiation General Medicine Embryonic stem cell Cell biology Protein Phosphatase 2C Alkaline phosphatase Signal transduction |
| Zdroj: | Journal of biochemistry. 165(6) |
| ISSN: | 1756-2651 |
| Popis: | 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-1/2 in 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. |
| Databáze: | OpenAIRE |
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