Glucocorticoid and Androgen Activation of Monoamine Oxidase A Is Regulated Differently by R1 and Sp1

Abstract

Monoamine oxidase (MAO)A Monoamine oxidase (MAO)2 is located on outer membranes of mitochondria in neuronal, glial, and other cells. It catalyzes the oxidative deamination of monoamine neurotransmitters such as serotonin, norepinephrine, dopamine, and phenylethylamine (1). MAO exists in two isoforms, MAO A and MAO B. MAO A preferentially oxidizes serotonin (5-hydroxytryptamine), norepinephrine, and dopamine and is irreversibly inhibited by low concentration of clorgyline (2). MAO B preferentially oxidizes phenylethylamine and benzylamine and is irreversibly inactivated by low concentrations of pargyline and deprenyl (3). MAO A and B are coded by different genes (4) closely linked on the X chromosome, Xp11.2-11.4 (5). Both genes consist of 15 exons with identical exonintron organization (6) and both are regulated by Sp1 factors; however, there are some differences in their cis-elements (7-9). The core promoter of MAO A consists of Sp1-binding sites that are activated by Sp1 (7) and repressed by a novel repressor R1 (RAM2/CDCA7L) (8). This core promoter has bi-directional activity (7). In addition, a functional polymorphism of a 30-bp repeat sequence has been identified and located ϳ1.2 kb upstream of the MAO A translation start site (10). The human MAO B promoter contains two clusters of overlapping Sp1 sites separated by a CACCC element (11). An Sp1-like transcription factor, transforming growth factor-␤-inducible early gene, also activates the MAO B promoter via overlapping Sp1 sites (12). The expression of MAO B is regulated by protein kinase C and the MAPK signaling pathway (13).A mutation in the human MAO A gene, which results in no enzymatic activity, is associated with aggressive behavior in males in a Dutch family (14). MAO A knock-out (KO) mice showed aggressive behavior in males (15), but MAO B KO mice did not show aggressive behavior (16). Interestingly, a spontaneous mutation of the MAO A gene in MAO B KO mice resulted in MAO A/B double KO mice, which showed hyperreactivity and anxiety-like behavior (12).Steroid hormones are involved in the regulation of many functions in which MAO also plays an important roles such as response to stress, behavioral adaptation and mood (17). Significant hypersecretion of glucocorticoids has been shown to be associated with depression (18). The synthetic glucocorticoid, dexamethasone, increases MAO A activity in human fibroblasts (19) and rat brain frontal cortex (20). Both anti-glucocorticoid agents (21) and MAO A inhibitors (22, 23) have been used in the treatment of depression. Androgens have also been shown to increase MAO activity in the rat brain (24).The biological action of glucocorticoids and androgens are mediated through their respective receptors, glucocorticoid receptor (GR) and androgen receptor (AR). GR and AR bind to derivatives of a common response element, i.e. the consensus glucocorticoid response element (GRE), 5Ј-GGTACAnnn-

Elevated Monoamine Oxidase A Binding During Major Depressive Episodes Is Associated with Greater Severity and Reversed Neurovegetative Symptoms

“…MAO-A level is highly correlated with MAO-A activity in brain (Nelson et al, 1979;Saura et al, 1992) and indices of MAO-A level in the prefrontal (PFC) and anterior cingulate cortex (ACC) were elevated by 25-40% across the three studies that investigated the most common, early onset MDD (Johnson et al, 2011;Meyer et al, 2006;Meyer et al, 2009). Elevated MAO-A level in these regions in MDE is consistent with other specific findings: MDE is a highstress state, and glucocorticoid administration increases transcription rate and catalytic activity of MAO-A in human neuroblastoma and glioblastoma cell lines (Ou et al, 2006a). Furthermore, glucocorticoid administration and/or chronic stress increase MAO-A mRNA and/or MAO-A protein levels in the PFC of rodents (Filipenko et al, 2002;Slotkin et al, 1998).…”

“…Even so, given that the most likely mechanism for elevated MAO-A in MDD is excessive glucocorticoid secretion, and glucocorticoids promote transcription of MAO-A in both of these general cell types, it is likely that severity is related to MAO-A level in both cell types. In addition, levels of the transcription factors implicated in greater MAO-A expression in MDD, such as reduced expression of R1 (a MAO-A repressor) and greater expression of Sp1 (a MAO-A activator), are similarly modulated by glucocorticoids in both glia and neurons (Ou et al, 2006a). A second limitation is that we selected MAO-A V T as a marker.…”

“…Thus, the association between elevated MAO-A V T in the PFC and ACC and reversed neurovegetative symptoms provides new directions to investigate their etiology, particularly for weight gain. A number of factors may lead to elevated MAO-A level or activity, including glucocorticoid administration, estrogen depletion and mitochondrial toxicity/ dysfunction (Fitzgerald et al, 2007;Ou et al, 2006a;Sacher et al, 2010). We suggest that the latter marker, if present throughout the body and brain, may be the best theoretical direction to investigate for weight gain because mitochondrial dysfunction in muscle has been identified in obesity and impaired mitochondrial function reduces the ability of muscle to be active and expend energy (Lowell and Shulman, 2005;Patti and Corvera, 2010).…”

Anti-inflammatory functions of glucocorticoid-induced genes

“…Composite GC responsive regions have been described in the promoters of tyrosine aminotransferase (Grange et al, 2001;Grange et al, 1989;Roux et al, 1995;Sassi et al, 1998) proliferin (Diamond et al, 1990), α1-acid glycoprotein (Alam et al, 1993;Nishio et al, 1993;Savoldi et al, 1997), the cyclin-dependent kinase inhibitor p21 waf1/cip1 Cram et al, 1998), β1-adrenergic receptor (Tseng et al, 2001), glucose-6-phosphate transporter (Kallwellis-Opara et al, 2003), pyruvate dehydrogenase kinase 4 (Kwon et al, 2004), monoamine oxidase (Manoli et al, 2005;Ou et al, 2006), β-casein (Rosen et al, 1998;Wyszomierski and Rosen, 2001) and others.…”

“…Recruitment to such sites is thought to be mediated by both protein-DNA interactions and protein-protein interactions of GR with other transcription factors. GR has been shown to cooperate with transcription factors of many different classes, including the zinc finger transcription factor, stimulatory protein 1 (Sp1) (Manoli et al, 2005;Marinovic et al, 2002;Ou et al, 2006), homeobox proteins (Subramaniam et al, 2003), ets-related proteins (Aittomaki et al, 2000;Aurrekoetxea-Hernandez and Buetti, 2004;Mullick et al, 2001), interferon response factors (Jiang et al, 2004), helix-loop-helix factors (Jiang et al, 2004;Tseng et al, 2001), members of the CCAAT/enhancer-binding protein (C/EBP), forkhead box (Fox) and signal transducer and activator of transcription (STAT) families, and even NFκB itself (Hofmann and Schmitz, 2002).…”