Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway

Abstract

Monoamine oxidase A (MAO A) degrades serotonin, norepinephrine, and dopamine and produces reactive oxygen that may cause neuronal cell death. We have previously reported that a novel transcription factor R1 (RAM2͞CDCA7L͞JPO2) inhibits the MAO A promoter and enzymatic activities. This study reports the roles of MAO A and R1 in apoptosis and proliferation. We have found that in serum starvation-induced apoptosis, p38 kinase, MAO A, and caspase-3 were increased, whereas Bcl-2 and R1 were reduced. Using a p38 kinase inhibitor, R1 overexpression, and MAO A inhibitor, we have shown that MAO A and R1 are downstream of p38 kinase and Bcl-2, but upstream of caspase-3. Inhibition of MAO A prevents cell apoptosis. This notion was further supported by the finding that serum starvation-induced apoptosis is reduced in cortical brain cells from MAO A-deficient mice compared with WT. In addition, we found that MAO A and R1 are involved in the c-Myc-induced proliferative signaling pathway in the presence of serum. Immunoprecipitation and immunohistochemistry experiments indicate that the oncogene c-Myc colocalizes with R1 and induces R1 gene expression. Using R1 overexpression, R1 small interfering RNA, and a MAO A inhibitor, we found that R1 and MAO A act upstream of cyclin D1 and E2F1. In summary, this study demonstrates the functions of MAO A and its repressor R1 in apoptotic signaling pathways.c-Myc ͉ caspase-3 ͉ p38 kinase ͉ proliferation ͉ transcription factor M onoamine oxidases (MAOs) A and B, located on the outer mitochondria membrane with a 70% amino acid sequence identity (1, 2), catalyze the oxidative deamination of biogenic and dietary amines including monoamine neurotransmitters serotonin, norepinephrine, dopamine, and phenylethylamine. MAO plays important roles in several psychiatric and neurological disorders (3). MAO exists in two forms, MAO A and MAO B. Their catalytic activity generates H 2 O 2 and nitrogen species, which are toxic products and may cause oxidative damage to mtDNA and have potential implications for apoptosis, aging, and neurodegenerative processes (4).The in vivo function of MAO A and MAO B has been studied extensively in MAO A and MAO B knockout (KO) mice (5-7). The regulation of MAO A and MAO B gene expression by extracellular stimulation, phorbol 12-myristate 13-acetate (PMA), has also been examined. PMA selectively increases MAO B but not MAO A gene expression by activation of protein kinase C and mitogen-activated protein kinase (MAPK) signaling pathways (8).Ample evidence has indicated an important role for MAO A in apoptosis. MAO A expression has been shown to increase after the depletion of neurotrophic factor mediated by p38 kinase in PC12 cells (9). A MAO A inhibitor, clorgyline, was able to protect cells from apoptosis induced by serum starvation in human melanoma m14 cells (10). More recently, MAO A has been found to be a target of a dopaminergic neurotoxin, N-methyl-(R)-salsolinol, which leads to apoptosis in a human neuroblastoma SH-SY5Y cell line (11). This apoptotic activity co...

Forebrain-specific Expression of Monoamine Oxidase A Reduces Neurotransmitter Levels, Restores the Brain Structure, and Rescues Aggressive Behavior in Monoamine Oxidase A-deficient Mice

“…These studies and our current study demonstrated that MAO A may be an important enzyme that regulates the brain structure at a critical neuronal developmental stage, which is important for the development of brain structures and behaviors in adults. In addition, we have found a new function of MAO A and its novel repressor R1 (RAM2/ CDCA7L/JPO 2 ) in apoptosis and c-Myc-induced cell cycle signaling pathway (38). The various MAO KO animal models generated, including MAO A KO, MAO B KO, MAO AB double KO, and forebrain-specific human MAO A transgenic MAO A KO generated here, would be valuable for further studying the role of MAO A and neurotransmitters, 5-HT, NE, and DA, in neuronal development, brain structure, and behavior.…”

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

“…In brain tissue, MAO-A level is highly correlated with MAO-A activity and MAO-A V T is primarily an index of MAO-A level (Saura et al, 1992). Elevated MAO-A activity is related to several important downstream effects, as MAO-A participates in the metabolism of serotonin, dopamine, and norepinephrine, produces the pro-oxidant hydrogen peroxide and influences the predisposition toward apoptosis (Fitzgerald et al, 2007;Ou et al, 2006b;Youdim et al, 2006). The specific regions assayed in this study, which have a reasonably high MAO-A density, also participate in neural systems dysregulated during MDE and elevations of MAO-A V T in these regions could potentially account for the individual symptoms of MDE.…”

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

“…After incubation with secondary antibody, stained slides were mounted with Vectashield in the presence of 4,6-diamino-2-phenylindole (DAPI nuclear stain, Vector Lab, Inc.) (17).…”