Evidence for involvement of ERK, PI3K, and RSK in induction of Bcl-2 by valproate.
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.
Creson
Thomas K
TK
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.
Yuan
Peixiong
P
Manji
Husseini K
HK
Chen
Guang
G
D000927:Anticonvulsants / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D019253:Proto-Oncogene Proteins c-bcl-2; D014635:Valproic Acid; D019869:Phosphatidylinositol 3-Kinases; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3