Faculty Collaboration Database

Mechanistic role for a novel glucocorticoid-KLF11 (TIEG2) protein pathway in stress-induced monoamine oxidase A expression. J Biol Chem 2012 Jul 13;287(29):24195-206

Date

05/26/2012

Pubmed ID

22628545

Pubmed Central ID

PMC3397846

DOI

10.1074/jbc.M112.373936

Scopus ID

2-s2.0-84863798866 (requires institutional sign-in at Scopus site)   78 Citations

Abstract

Chronic stress is a risk factor for psychiatric illnesses, including depressive disorders, and is characterized by increased blood glucocorticoids and brain monoamine oxidase A (MAO A, which degrades monoamine neurotransmitters). This study elucidates the relationship between stress-induced MAO A and the transcription factor Kruppel-like factor 11 (KLF11, also called TIEG2, a member of the Sp/KLF- family), which inhibits cell growth. We report that 1) a glucocorticoid (dexamethasone) increases KLF11 mRNA and protein levels in cultured neuronal cells; 2) overexpressing KLF11 increases levels of MAO A mRNA and enzymatic activity, which is further enhanced by glucocorticoids; in contrast, siRNA-mediated KLF11 knockdown reduces glucocorticoid-induced MAO A expression in cultured neurons; 3) induction of KLF11 and translocation of KLF11 from the cytoplasm to the nucleus are key regulatory mechanisms leading to increased MAO A catalytic activity and mRNA levels because of direct activation of the MAO A promoter via Sp/KLF-binding sites; 4) KLF11 knockout mice show reduced MAO A mRNA and catalytic activity in the brain cortex compared with wild-type mice; and 5) exposure to chronic social defeat stress induces blood glucocorticoids and activates the KLF11 pathway in the rat brain, which results in increased MAO A mRNA and enzymatic activity. Thus, this study reveals for the first time that KLF11 is an MAO A regulator and is produced in response to neuronal stress, which transcriptionally activates MAO A. The novel glucocorticoid-KLF11-MAO A pathway may play a crucial role in modulating distinct pathophysiological steps in stress-related disorders.

Author List

Grunewald M, Johnson S, Lu D, Wang Z, Lomberk G, Albert PR, Stockmeier CA, Meyer JH, Urrutia R, Miczek KA, Austin MC, Wang J, Paul IA, Woolverton WL, Seo S, Sittman DB, Ou XM

Author

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis Regulatory Proteins
Blotting, Western
Cell Cycle Proteins
Cell Line, Tumor
Cells, Cultured
Chromatin Immunoprecipitation
Chromatography, High Pressure Liquid
Corticosterone
DNA-Binding Proteins
Dexamethasone
Fluorescent Antibody Technique
Gene Expression
Humans
Male
Mice
Mice, Knockout
Monoamine Oxidase
Radioimmunoassay
Rats
Rats, Wistar
Real-Time Polymerase Chain Reaction
Repressor Proteins
Serotonin
Stress, Physiological
Transcription Factors