Valproic acid induces monoamine oxidase A via Akt/forkhead box O1 activation

Jason Boyang Wu; Jean C Shih

doi:10.1124/mol.111.072744

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Valproic acid induces monoamine oxidase A via Akt/forkhead box O1 activation

Journal article

Open access

Peer reviewed

Valproic acid induces monoamine oxidase A via Akt/forkhead box O1 activation

Jason Boyang Wu and Jean C Shih

Molecular pharmacology, Vol.80(4), pp.714-723

10/2011

DOI: https://doi.org/10.1124/mol.111.072744

PMID: 21775495

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Abstract

Binding Sites - drug effects

Binding Sites - physiology

Cell Line, Tumor

Cells, Cultured

Enzyme Induction - drug effects

Enzyme Induction - physiology

Forkhead Box Protein O1

Forkhead Transcription Factors - metabolism

Gene Knockdown Techniques - methods

Monoamine Oxidase - biosynthesis

Proto-Oncogene Proteins c-akt - metabolism

Rats

Valproic Acid - pharmacology

Valproic acid (VPA) has been widely used in clinics for the treatment of multiple neuropsychiatric disorders, such as epilepsy and bipolar disorder. One of the mechanisms by which VPA exerts its effect is through regulating the brain levels of serotonin. However, the molecular basis of this VPA action is not fully understood. Here, we report for the first time that VPA activates monoamine oxidase (MAO) A catalytic activity, mRNA level, and promoter activity. MAO A is a key enzyme that degrades a number of monoamine neurotransmitters, including serotonin. Our results show that VPA increased the phosphorylation of both Akt and Forkhead box O1 (FoxO1), whereas pretreatment of cells with 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) (a phosphoinositide 3-kinase inhibitor) reduced the VPA activation of MAO A. Overexpression of FoxO1 dramatically repressed both the basal and VPA-induced MAO A catalytic and promoter activities to 30 to 60%. Small interfering RNA knockdown of FoxO1 attenuated the stimulating effect of VPA on MAO A. Moreover, introduction of a constitutively active form of FoxO1 abolished the activation of MAO A by VPA and Akt. These results suggest that FoxO1 is a repressor for MAO A transcription, and its phosphorylation is involved in VPA activation of MAO A. Sequence analysis, electrophoretic mobility shift and chromatin immunoprecipitation assays further showed the presence of a functional FoxO1-binding site in MAO A core promoter. Taken together, these results demonstrate that MAO A is a novel target for VPA via Akt/FoxO1 signaling pathway. This information provides new insights into the pharmacological mechanisms and therapeutic implications of VPA action.

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Title: Valproic acid induces monoamine oxidase A via Akt/forkhead box O1 activation
Creators: Jason Boyang Wu - Washington State University, Pharmaceutical Sciences, Department of
Jean C Shih - University of Southern California
Publication Details: Molecular pharmacology, Vol.80(4), pp.714-723
Academic Unit: Pharmacy and Pharmaceutical Sciences, College of
Grant note: R01 MH067968 / NIMH NIH HHS R01MH67968 / NIMH NIH HHS R01MH39085 / NIMH NIH HHS R01 MH039085 / NIMH NIH HHS
Identifiers: 99900620488901842
Language: English
Resource Type: Journal article