Vitamin D3 signalling in the brain enhances the function of phosphoprotein enriched in astrocytes--15 kD (PEA-15)

In spite of growing evidence linking vitamin D(3) levels to mental health disorders, little is known about its direct targets in the brain. This study set out to investigate targets of vitamin D(3) 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 D(3), such as cyclin-dependent protein-serine kinase 1/2, epidermal growth factor receptor-tyrosine kinase, protein kinase A, protein-serine kinase Bgamma and protein-serine kinase Calpha. 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 D(3) receptor, suggesting a strong vitamin D(3) dependency of the PEA-15 promoter. PEA-15 up-regulation by vitamin D(3) 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 D(3) 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 D(3) relevant for apoptosis and cell proliferation, and thus strongly supports a function of vitamin D(3) in the brain that impacts on processes highly relevant for major neurological disorders.