Mechanistic Role for a Novel Glucocorticoid-KLF11 (TIEG2) Protein Pathway in Stress-induced Monoamine Oxidase A Expression

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

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287(29): 24195-24206.

DOI：10.1074/jbc.M112.373936

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 MAOA 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.

• 出版日期2012-7-13