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

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. Background: The function of KLF11/TIEG2 under stressful conditions is undefined. Results: KLF11 increases brain MAO expression through its promoter and a chromatin partner, which can be enhanced by stress. Conclusion: This is the first elucidation of mechanisms underlying stress-induced KLF11-MAO up-regulation. Significance: This novel KLF11-MAO pathway may play an important role in stress-related brain disorders.