Vitamin D3 signalling in the brain enhances the function of phosphoprotein enriched in astrocytes – 15 kD (PEA-15)
Darja Obradovic
Max Planck Institute of Psychiatry, Munich, Germany
Search for more papers by this authorCiro Zanca
Department of Cellular and Molecular Biology and Pathology, Federico II University of Naples, and IEOS, CNR, Naples, Italy
C.Z. is co–first author; G.C. is co–principal investigator.
Search for more papers by this authorAnnette Vogl
Max Planck Institute of Psychiatry, Munich, Germany
Search for more papers by this authorDietrich Trümbach
Helmholtz Zentrum München – German Research Center for Environmental Health – Institute for Developmental Genetics, Neuherberg, Germany
Search for more papers by this authorJan Deussing
Max Planck Institute of Psychiatry, Munich, Germany
Search for more papers by this authorGerolama Condorelli
Department of Cellular and Molecular Biology and Pathology, Federico II University of Naples, and IEOS, CNR, Naples, Italy
C.Z. is co–first author; G.C. is co–principal investigator.
Search for more papers by this authorCorresponding Author
Theo Rein
Max Planck Institute of Psychiatry, Munich, Germany
Correspondence to: Theo REIN, Max Planck Institute of Psychiatry, 80804 Munich, Germany.Tel.: +49-89-30622-531 Fax: +49-89-30622-610E-mail: [email protected]Search for more papers by this authorDarja Obradovic
Max Planck Institute of Psychiatry, Munich, Germany
Search for more papers by this authorCiro Zanca
Department of Cellular and Molecular Biology and Pathology, Federico II University of Naples, and IEOS, CNR, Naples, Italy
C.Z. is co–first author; G.C. is co–principal investigator.
Search for more papers by this authorAnnette Vogl
Max Planck Institute of Psychiatry, Munich, Germany
Search for more papers by this authorDietrich Trümbach
Helmholtz Zentrum München – German Research Center for Environmental Health – Institute for Developmental Genetics, Neuherberg, Germany
Search for more papers by this authorJan Deussing
Max Planck Institute of Psychiatry, Munich, Germany
Search for more papers by this authorGerolama Condorelli
Department of Cellular and Molecular Biology and Pathology, Federico II University of Naples, and IEOS, CNR, Naples, Italy
C.Z. is co–first author; G.C. is co–principal investigator.
Search for more papers by this authorCorresponding Author
Theo Rein
Max Planck Institute of Psychiatry, Munich, Germany
Correspondence to: Theo REIN, Max Planck Institute of Psychiatry, 80804 Munich, Germany.Tel.: +49-89-30622-531 Fax: +49-89-30622-610E-mail: [email protected]Search for more papers by this authorAbstract
In spite of growing evidence linking vitamin D3 levels to mental health disorders, little is known about its direct targets in the brain. This study set out to investigate targets of vitamin D3 in a human brain stem cell line. We employed arrays with antibodies directed against more than 600 structural and signalling proteins, including phospho-variants. Over 180 proteins responded to vitamin D3, such as cyclin-dependent protein-serine kinase 1/2, epidermal growth factor receptor-tyrosine kinase, protein kinase A, protein-serine kinase Bγ and protein-serine kinase Cα. PEA-15 (phosphoprotein enriched in astrocytes-15 kD, also known as PED), known to be involved in various anti-proliferative and anti-apoptotic effects, was strongly up-regulated. In silico promoter analysis revealed conserved binding sites for vitamin D3 receptor, suggesting a strong vitamin D3 dependency of the PEA-15 promoter. PEA-15 up-regulation by vitamin D3 could be confirmed by Western blot in two different cell lines. Analysis of mRNA and protein phosphorylation status of PEA-15 suggests that increased PEA-15 promoter activity and increased protein stabilization contribute to the overall rise of PEA-15 protein. In a functional test of this novel pathway, we demonstrated that vitamin D3 was able to rescue cells from TRAIL-induced apoptosis through regulation of the PEA-15 expression and function. Summarized, our study presents novel targets of vitamin D3 relevant for apoptosis and cell proliferation, and thus strongly supports a function of vitamin D3 in the brain that impacts on processes highly relevant for major neurological disorders.
Supporting Information
Table S1. Antibody array ? full list.
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| JCMM_753_sm_Table1.xls387 KB | Supporting info item |
| JCMM_753_sm_ATT00001.c299 B | Supporting info item |
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