Evidence for Involvement of ERK, PI3K, and RSK in Induction of Bcl-2 by Valproate

• Published in: Journal of molecular neuroscience 2009-02, Vol.37 (2), p.123-134
• Main Authors: Creson, Thomas K., Yuan, Peixiong, Manji, Husseini K., Chen, Guang
• Format: Article
• Language: English
• Subjects: Anticonvulsants - pharmacology; Binding sites; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Line, Tumor; Dose-Response Relationship, Drug; Genes, Reporter; Humans; Kinases; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Neuroblastoma; Neurochemistry; Neurology; Neurons - drug effects; Neurons - enzymology; Neurosciences; Phosphatidylinositol 3-Kinases - metabolism; Promoter Regions, Genetic; Proteins; Proteomics; Proto-Oncogene Proteins c-bcl-2 - genetics; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; Valproic Acid - pharmacology
• ISSN: 0895-8696; 1559-1166
• DOI: 10.1007/s12031-008-9122-2

Valproate, an anticonvulsant and mood stabilizer, up-regulates Bcl-2, a neurotrophic/neuroprotective protein. In this study, we investigated the molecular mechanism through which Bcl-2 is up-regulated by valproate using cultured human neuron-like cells. Valproate, within therapeutically relevant ranges, induced time- and concentration-dependent up-regulations of both Bcl-2 messenger RNA and protein implicating an underlying gene transcriptional-mediated mechanism. Bcl-2 up-regulations were associated with ERK1/2 and PI3K pathway activations and elevated levels of activated phospho-RSK and phospho-CREB, convergent targets of the ERK1/2 and PI3K pathways. Valproate increased transcriptional activity of a human bcl-2 promoter–reporter gene construct. This effect was attenuated, but not blocked, by mutation of a CREB DNA binding site, a CRE site in the human bcl-2 promoter sequence. ERK and/or PI3K pathway inhibitors and RSK1 small hairpin RNA knockdown reduced, but did not abolish, baseline and valproate-induced promoter activities and lowered Bcl-2 protein levels. These data collectively suggest that valproate induces Bcl-2 regulation partially through activations of the ERK and PI3K cascades and their convergent kinase, RSK, although other unknown mechanism(s) are likely involved. Given the known roles of Bcl-2 in the central nervous system, the current findings offer a partial yet complex molecular mechanistic explanation for the known neurobiological effects of valproate including neurite growth, neuronal survival, and neurogenesis.