Mechanistic role for a novel glucocorticoid-KLF11 (TIEG2) protein pathway in stress-induced monoamine oxidase A expression

Matthew Grunewald, Shakevia Johnson, Deyin Lu, Zhe Wang, Gwen Lomberk, Paul R. Albert, Craig A. Stockmeier, Jeffrey H. Meyer, Raul Urrutia, Klaus A. Miczek, Mark C. Austin, Junming Wang, Ian A. Paul, William L. Woolverton, Seungmae Seo, Donald B. Sittman, Xiao Ming Ou

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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 knock-down 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 MAOA. The novel glucocorticoid-KLF11-MAOA pathway may play a crucial role in modulating distinct pathophysiological steps in stress-related disorders.

Original languageEnglish (US)
Pages (from-to)24195-24206
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number29
DOIs
StatePublished - Jul 13 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Grunewald, M., Johnson, S., Lu, D., Wang, Z., Lomberk, G., Albert, P. R., Stockmeier, C. A., Meyer, J. H., Urrutia, R., Miczek, K. A., Austin, M. C., Wang, J., Paul, I. A., Woolverton, W. L., Seo, S., Sittman, D. B., & Ou, X. M. (2012). Mechanistic role for a novel glucocorticoid-KLF11 (TIEG2) protein pathway in stress-induced monoamine oxidase A expression. Journal of Biological Chemistry, 287(29), 24195-24206. https://doi.org/10.1074/jbc.M112.373936