TY - JOUR
T1 - Mechanistic role for a novel glucocorticoid-KLF11 (TIEG2) protein pathway in stress-induced monoamine oxidase A expression
AU - Grunewald, Matthew
AU - Johnson, Shakevia
AU - Lu, Deyin
AU - Wang, Zhe
AU - Lomberk, Gwen
AU - Albert, Paul R.
AU - Stockmeier, Craig A.
AU - Meyer, Jeffrey H.
AU - Urrutia, Raul
AU - Miczek, Klaus A.
AU - Austin, Mark C.
AU - Wang, Junming
AU - Paul, Ian A.
AU - Woolverton, William L.
AU - Seo, Seungmae
AU - Sittman, Donald B.
AU - Ou, Xiao Ming
PY - 2012/7/13
Y1 - 2012/7/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84863798866&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863798866&partnerID=8YFLogxK
U2 - 10.1074/jbc.M112.373936
DO - 10.1074/jbc.M112.373936
M3 - Article
C2 - 22628545
AN - SCOPUS:84863798866
SN - 0021-9258
VL - 287
SP - 24195
EP - 24206
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 29
ER -