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

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Abstract

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.

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Abbreviations

Bcl-2:

B-cell lymphoma 2

BD:

bipolar (mood) disorder

CRE:

cyclic adenosine monophosphate response element

CREB:

cyclic adenosine monophosphate response element binding protein

ERK:

extracellular signal-regulated kinase

GSK-3:

glycogen synthase kinase-3

HDAC:

histone deacetylase

IMPase:

inositol monophosphatase

PI3K:

phosphatidylinositol 3-kinase

RSK:

p90 ribosomal S6 kinase

VPA:

valproate

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Acknowledgments

This work was supported by the NIMH intramural program (Manji and Chen) and a NARSAD research award (Chen).

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  1. Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, 35 Convent Drive, Bldg 35, Rm 1C-912, Bethesda, MD, 20892-3711, USA

    Thomas K. Creson, Peixiong Yuan, Husseini K. Manji & Guang Chen

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  1. Thomas K. Creson
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  2. Peixiong Yuan
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  3. Husseini K. Manji
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  4. Guang Chen
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Correspondence to Guang Chen.

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Creson, T.K., Yuan, P., Manji, H.K. et al. Evidence for Involvement of ERK, PI3K, and RSK in Induction of Bcl-2 by Valproate. J Mol Neurosci 37, 123–134 (2009). https://doi.org/10.1007/s12031-008-9122-2

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