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Organization of MAO A and MAO B Promoters and Regulation of Gene Expression
NeuroToxicology 25 (2004) 31–36
Organization of MAO A and MAO B Promoters and Regulation of Gene Expression Kevin Chen* Department of Molecular Pharmacology and Toxicology, Pharmaceutical Science Center, University of Southern California, 1985 Zonal Avenue Los Angeles, CA 90033, USA
Abstract Monoamine oxidase (MAO) A and B play important roles in the metabolism of catecholamines and xenobiotics in the central nervous system and peripheral tissues. The ubiquitous presence of low level of MAO in all cells suggests essential functional for house keeping. Higher level of expression of MAO A and B also were observed in tissue and cell specific manner. The core promoter of human MAO A and B promoters have been characterized. Sp1 binding motifs were present in both promoters which constituted the major binding sites for Sp1 and Sp1-like family transcription factor binding, and other interaction proteins like Egr-1 in MAO B promoter. The presence of repeat units within the 2 kb human MAO A promoter which is associated with promoter activity and enzymatic activity in human fibroblast culture provided a tool to study human population with abnormal behaviors related to serotonin and other neurotransmitters. Conflicting results were reported from these studies due to the lack of basic understanding of MAO A promoter and the factors such as glucocorticoid which influences MAO A activity. Hopefully the enthusiasm will lead to more reliable tools to identify the major factor which caused the large difference in MAO A activity among human population. The overlapping Sp1/Egr-1/Sp1 binding site within MAO B promoter has been identified as the responsible element for PMA response. MAO B expression is selectively induced by the activation of protein kinase C and MAPK signal pathway. # 2003 Published by Elsevier Inc.
Keywords: Monoamine oxidase (MAO); Gene expression; Protein kinase C
INTRODUCTION Monoamine oxidase (MAO) A and B (flavin-containing deaminating amine: oxygen oxidoreductase, EC1.4.3.4.), catalyze the oxidative deamination of a number of neurotransmitters, dietary amines and xenobiotics including the Parkinsonism-producing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridene accompanied by release of hydrogen peroxide (H2O2) (Cohen, 1983). Both forms are located in the outer mitochondrial membrane and are distinguished by their substrate preference and sensitivity to inhibitors. MAO A preferentially oxidizes serotonin and norepinephrine and is inhibited by low concentrations of clorgyline (Johnston, 1968). MAO B has higher affinity for phenylethylamine and benzylamine, and is inhibited by low concentration of deprenyl (Knoll *
Tel.: þ1-323-442-1986; fax: þ1-323-224-7473. E-mail address: [email protected] (K. Chen). 0161-813X/$ – see front matter # 2003 Published by Elsevier Inc. doi:10.1016/S0161-813X(03)00113-X
and Magyer, 1972). Common substrates of MAO A and B include tyramine and dopamine. The deamination of neurotransmitter serotonin, dopamine, and norepinephrine suggests the important role of MAO in maintaining the homeosis of these neurotransmitters and the signal transduction pathways they involved. H2O2 produced during the oxidative deamination of catecholamine appears to be involved in the progress of neurodegenerative disorders, such as Parkinson disease and via oxidative damage to the mitochondrial membrane and DNA (Hauptmann et al., 1996). Cloning of the cDNAs for MAO A and B demonstrates that these two forms of the enzyme are coded by different genes (Bach et al., 1988) which were derived from the same ancestral gene (Grimsby et al., 1991). Both genes are located on the x chromosome at Xp11.23 to Xp22.1 in tail to tail orientation (Chen et al., 1992). MAO A and B transcripts were detected in most human tissues examined this suggests a functional need to eliminate their substrates (Grimsby et al., 1990).
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However, they do show different tissue and cell distribution. MAO A is predominantly found in catecholaminergic neurons, and MAO B is most abundant in serotonergic and histaminergic neurons and glial cells (Saura et al., 1994). The highest expression of MAO A was in placenta and MAO B is specific in platelets and lymphocytes (Sullivan et al., 1978). Deletion of MAO A activity in males in a Dutch family resulted abnormal aggressiveness (Brunner et al., 1993). Aggressive behavior was also observed in MAO A deficient mice (Cases et al., 1995) and not observed in MAO B knock out mice (Grimsby et al., 1997; Shih et al., 1999). A new function of MAO that is related to imidazole binding has recently been suggested (Raddatz et al., 1995). The cell and tissue specific expression of MAO is encoded within the gene and the promoter. The DNA sequence of the promoter contents the binding motif for different transcription factors which interacts with transcription machinery and determines the level of gene expression. This review will discuss the promoter organization of human MAO A and B and their expression in the cell lines selected for study. Entrez-PubMed database search was based on the following keywords: monoamine oxidase, promoter, and gene expression.
IDENTIFICATION OF HUMAN MAO A AND B GENE CORE PROMOTERS Using a series of 50 flanking sequences linked to a human growth hormone reporter gene, the DNA sequence responsible for the transcription activation of MAO A and B genes were identified. When these constructs were transfected into NIH3T3, SHSY-5Y, and COS 7 cells, the maximal promoter activity for MAO A and B was found in a 0.14 kb PvuII/DraII and 0.15 kb PstI/NaeI fragment, respectively (Zhu et al., 1992). Both fragments are GC rich, contain potential Sp1 binding sites, and share approximately 60% sequence identity. However, the organization of the transcription elements is distinctly different between these two promoters. The MAO A 0.14 kb fragment lacks a TATA box, consists of three Sp1 elements (Yoshida et al., 2002) (Denney et al., 1994), and exhibits bi-directional promoter activity (Zhu et al., 1994). Additional Sp1 sites, CACCC elements, CCAAT boxes, and four 30 bp direct repeats are found in fartherupstream sequences in MAO A core promoter (Zhu and Shih, 1997). MAO B core promoter 0.15 kb fragment consists of two clusters of overlapping Sp1 sites separated by a CACCC element. The different promoter
organization of MAO A and B genes may underlie their different tissue- and cell-specific expression (Zhu et al., 1992). The MAO B core promoter constructs was used to test the ethanol treatment of SHSY-5Y neuroblastoma cells and MG1242 glioma cells. An increase of 2–3fold reporter gene expression and enzyme activity were observed after ethanol treatment of transfected cells. Gel retardation analysis with B0.15 fragment showed that ethanol caused changes in transcription factor binding to the MAO B core promoter in both cell lines in a cell-type specific fashion (Ekblom et al., 1996). The same B0.15 fragment was used to perform gel shift assays using nuclear extracts from human brain and lymphocytes. The binding patterns of two uncharacterized transcription factors were correlated between monoamine oxidase B enzyme activity in platelets (Ekblom et al., 1998). It will be interesting to characterize these unknown factors to understand the significance.
DIFFERENT REPORTER SYSTEM MAY RESULT IN DIFFERENT MAO A PROMOTER ACTIVITY MAO A-luciferase reporter constructs that contained all the known transcription initiation sites exhibited no evidence for inhibitory cis-elements between 200 and at least 935. The apparent inhibitory activity previously reported for sequences 50 to the most proximal PvuII site may have resulted from the use of partial promoter constructs that omitted the putative Inr element located between 30 and 40 bp 50 to the ATG codon (Denney et al., 1994). In MAO A-human growth hormone reporter constructs with or without the Inrlike sequence, the promoter activity decreases significantly in the cell lines tested. These results suggest that although the Inr-like sequence is present in the human MAO A promote, it acts as a negative cis-element instead of a transcription initiator (Zhu and Shih, 1997). The human growth hormone reporter system may also have some unknown elements within the vector sequence which is not a popular reporter system compare with dual-luciferase system.
A FUNCTIONAL POLYMORPHISM IN THE MAO A GENE PROMOTER An extensive repeat structure contained in two 90 bp repeats was present in the MAO A promoter sequence
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which down-regulates human MAO A promoter activity (Zhu and Shih, 1997). This polymorphism located 1.2 kb upstream of the MAO A coding sequences, consists of a 30 bp repeated sequence present in 3, 3.5, 4 or 5 copies in from different individuals across ethnic groups. The polymorphism has been shown to affect the transcriptional activity of the MAO A gene promoter in an luciferase assay system. Alleles with 3.5 or 4 copies of the repeat sequence are transcribed 2–10 times more efficiently than those with 3 or 5 copies of the repeat, suggesting an optimal length for the regulatory region (Sabol et al., 1998). This functional association of MAO A promoter activity and polymorphism became a useful genetic marker for PCR based analysis using genomic DNA from human population of behavior interests. These include aggression (Manuck et al., 2000), alcoholism (Koller et al., 2003; Lu et al., 2002; Parsian et al., 2003; Saito et al., 2002), antisocial alcoholism (Samochowiec et al., 1999), antisocial and anxious-depressive alcoholics (Schmidt et al., 2000), attention deficit (Lawson et al., 2003), attention deficit hyperactivity disorder (Manor et al., 2002), autism (Yirmiya et al., 2002), bipolar affective disorder (Furlong et al., 1999; Ho et al., 2000; Kirov et al., 1999), idiopathic generalized epilepsy (Haug et al., 2000), depression (Muller et al., 2002), major depressive disorder (Yoshida et al., 2002), mood disorder (Kunugi et al., 1999), panic disorder (Hamilton et al., 2000; Norton et al., 1999; Sand et al., 2000), restless legs syndrome (Desautels et al., 2002), schizophrenia (Norton et al., 2002), smoking (Ito et al., 2003), and psychiatric disorders (Syagailo et al., 2001). The number of publication is still increasing and conflicting results is very common because most of the sample in the studies listed is small and the human behavior analyzed involves multiple genes, MAO A is just one of the gene involved (Williams et al., 2003). More detailed understanding on the transcription factors involved in the 2 kb MAO A promoter is necessary before more answer can be obtained. The MAO A promoter tandem repeat region has been associated with the MAO A activity in human male skin fibroblasts. The median MAO A activity in cultures with three repeats was significantly lower than that in cultures with four repeats (Denney et al., 1999). This is consistent with published evidence that MAO A promoter constructs bearing three repeats have lower transcriptional activity in transfected neuroblastoma and choriocarcinoma cells (Sabol et al., 1998). The promoter tandem repeat may also participate differentially in the regulation of dopamine and serotonin turnover rates under presumed steady state in the
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central nervous system (Jonsson et al., 2000). However, no association of the variants and the resulting haplotypes with expression levels and enzyme activities of MAO A in human cortical brain autopsies (Balciuniene et al., 2002). Despite all the conflicting results surrounding the MAO A promoter polymorphism, a hypothesis was proposed that the effect of MAO A gene would be more readily revealed if the environment were explicitly taken into account. A large sample of male children from birth to adulthood was followed for 26 years to determine why some children who are maltreated grow up to develop antisocial behavior, whereas others do not. Although the MAO A genotype by itself was not correlated with antisocial behavior, the individuals with both a low-MAO A activity genotype and previous maltreatment were by far the most likely to have committed a violent crime and to be diagnosed with conduct disorder (Caspi et al., 2002). Hopefully more cohorts will be available to verify this finding. All these associated studies is base on the assumption that the brain MAO A enzymatic activity might be associated with human neuropsychiatric disorders and behavioral traits (Shih and Thompson, 1999). It is known that MAO A activity levels are highly variable among humans. Up to 100-fold (Castro Costa et al., 1980) and 515-fold (Denney et al., 1999) differences in MAO A activity have been detected in cultured skin fibroblasts which is the only non-invasive method to obtain the MAO A enzymatic activity for human. It has been proposed that the individual variation of MAO A activity levels is determined by genetic components (Hotamisligil and Breakefield, 1991), but our knowledge about the regulation of MAO A activity in human brain is still limited simply because the samples are not readily available. The cell culture system is still the only method which will help us to understand the molecular mechanism regulating the MAO A expression.
REGULATION OF HUMAN MAO B GENE BY Sp1 AND Sp3 As previously showed that the 246/99 MAO B promoter region exhibited the highest activity and contained two clusters of overlapping Sp1 sites, a CACCC element and a TATA box. Analysis of nine site-directed mutations of 246/99 region reveals that both clusters of Sp1 sites contribute positively whereas the CACCC element contributes negatively to the transcriptional activity. Gel shift analysis demonstrates that in addition to Sp1, Sp3 can interact with
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both clusters of Sp1 sites. Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2. These results suggest that the binding to the overlapping Sp1 sites by various members of Sp family is important for the regulation of the MAO B gene expression in human astrocytoma (MG1242) and hepatocytoma (HepG2) and cervical adenocarcinoma (HeLa) cell lines (Wong et al., 2001). Additional potential regulatory elements, including AP1, AP4, CAAT, GATA, upstream stimulatory factor (USF), estrogen receptor (ER), and sex-determining region Y-box5 (Sox5) were identified within the 2 kb 50 flanking sequence. The function of these potential elements will be tested when appropriate cell lines become available.
ACTIVATION OF HUMAN MAO B GENE BY A PROTEIN KINASE C MAPK SIGNAL TRANSDUCTION PATHWAY Phorbol-12-myristate-13-acetate (PMA) increases human MAO B but not MAO A gene expression. The sequence between 246 and 225 bp consists of overlapping binding sites (Sp1/Egr-1/Sp1) that are recognized by Sp1, Sp3, and PMA-inducible Egr-1 is essential for PMA activation. PMA transiently increases Egr-1 and c-jun gene expression. Site directed mutations show that Egr-1 and c-Jun transactivate the MAO B promoter and increase endogenous MAO B transcripts via the Sp1/Egr-1/Sp1 overlapping binding sites. Sp3 inhibits Sp1 and Egr-1 activation of MAO B gene expression. c-fos gene expression was increased by PMA but not involved in MAO B gene transcription. Furthermore, protein kinase C inhibitor blocks the PMA dependent activation of MAO B. Cotransfection of the MAO B promoter with dominant negative forms of Ras, Raf-1, MEKK1, MEK1, MEK3, MEK7, ERK2, JNK1, and p38/RK inhibit the PMA dependent activation of the MAO B promoter. These results indicate that MAO B expression is selectively induced by the activation of protein kinase C and MAPK signaling pathway and that c-Jun and Egr-1 appear to be the ultimate targets of this regulation in HepG2 cell line (Wong et al., 2002). The Sp1/Egr-1/Sp1 overlapping binding sites has been used as a bait in a yeast one-hybrid vector to screen an expression library. Many positive clones were obtained. One of
them contain Zinc finger binding motif and nuclear localization signals. This protein may belong to a new Sp1-like protein family (Cook et al., 1999). The function of this protein and its influence on MAO B is under investigation.
STEROID HORMONES INFLUENCE MAO ENZYMATIC ACTIVITY In human skin fibroblasts, the original undetectable MAO A enzymatic activity can be elevated to detectable level by dexamethasone treatment (Edelstein and Breakefield, 1986). Careful examine the 2 kb MAO A promoter region reveals three potential glucocorticoid response elements. It is important to identified the function of these elements because the hormonal influence of MAO enzymatic activity will certainly alter the concentration of neurotransmitters in the brain which may change the mental status. The glucocorticoid response has also been reported in MAO B in cultured rat astrocytes (Carlo et al., 1996). The MAO B activity increases by retinoic acid treatment in cultured chicken hepatocytes has also been reported (Nicotra et al., 2002). There is a 20-fold difference in MAO A expression between androgen dependent and independent prostate cancer LNCaP cell lines (Vaarala et al., 2000). The expression of MAO in female will be interesting because there are two X-chromosomes present in females. Additional regulation on the promoter involving X-chromosome inactivation will increase the complexity for analysis. As mentioned earlier, the potential estrogen receptor binding site has been identified within the 2 kb MAO B promoter region. The proper cell lines of female origin will be discovered to demonstrate the function of this potential binding element.
SUMMARY AND FUTURE PROSPECTIVE In the preceding sections, the current knowledge on MAO A and B promoter has been reviewed. The Sp1 family transcription factors were identified to be the major players regulating both MAO A and B promoters. However, the information encoded within the MAO genes should content all the blueprints for their temporal and special expression pattern within the proper cell lineage, the ability to response to the physiological changes such as hormones, glucose concentration, neurotransmitters, oxygen tension, temperature, etc. These complex signal interactions can be
K. Chen / NeuroToxicology 25 (2004) 31–36
accomplished through different signal transduction pathway via protein–protein, protein–DNA interactions, and protein modification and intracellular translocation. There are a lot of work need to be accomplished before we can have satisfactory answer to the molecular mechanism of tissue specific expression of MAOs.
ACKNOWLEDGEMENTS The author would like to thank Jean C. Shih for support and encouragements.
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Organization of MAO A and MAO B Promoters and Regulation of Gene Expression Kevin Chen* Department of Molecular Pharmacology and Toxicology, Pharmaceutical Science Center, University of Southern California, 1985 Zonal Avenue Los Angeles, CA 90033, USA
Abstract Monoamine oxidase (MAO) A and B play important roles in the metabolism of catecholamines and xenobiotics in the central nervous system and peripheral tissues. The ubiquitous presence of low level of MAO in all cells suggests essential functional for house keeping. Higher level of expression of MAO A and B also were observed in tissue and cell specific manner. The core promoter of human MAO A and B promoters have been characterized. Sp1 binding motifs were present in both promoters which constituted the major binding sites for Sp1 and Sp1-like family transcription factor binding, and other interaction proteins like Egr-1 in MAO B promoter. The presence of repeat units within the 2 kb human MAO A promoter which is associated with promoter activity and enzymatic activity in human fibroblast culture provided a tool to study human population with abnormal behaviors related to serotonin and other neurotransmitters. Conflicting results were reported from these studies due to the lack of basic understanding of MAO A promoter and the factors such as glucocorticoid which influences MAO A activity. Hopefully the enthusiasm will lead to more reliable tools to identify the major factor which caused the large difference in MAO A activity among human population. The overlapping Sp1/Egr-1/Sp1 binding site within MAO B promoter has been identified as the responsible element for PMA response. MAO B expression is selectively induced by the activation of protein kinase C and MAPK signal pathway. # 2003 Published by Elsevier Inc.
Keywords: Monoamine oxidase (MAO); Gene expression; Protein kinase C
INTRODUCTION Monoamine oxidase (MAO) A and B (flavin-containing deaminating amine: oxygen oxidoreductase, EC1.4.3.4.), catalyze the oxidative deamination of a number of neurotransmitters, dietary amines and xenobiotics including the Parkinsonism-producing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridene accompanied by release of hydrogen peroxide (H2O2) (Cohen, 1983). Both forms are located in the outer mitochondrial membrane and are distinguished by their substrate preference and sensitivity to inhibitors. MAO A preferentially oxidizes serotonin and norepinephrine and is inhibited by low concentrations of clorgyline (Johnston, 1968). MAO B has higher affinity for phenylethylamine and benzylamine, and is inhibited by low concentration of deprenyl (Knoll *
Tel.: þ1-323-442-1986; fax: þ1-323-224-7473. E-mail address: [email protected] (K. Chen). 0161-813X/$ – see front matter # 2003 Published by Elsevier Inc. doi:10.1016/S0161-813X(03)00113-X
and Magyer, 1972). Common substrates of MAO A and B include tyramine and dopamine. The deamination of neurotransmitter serotonin, dopamine, and norepinephrine suggests the important role of MAO in maintaining the homeosis of these neurotransmitters and the signal transduction pathways they involved. H2O2 produced during the oxidative deamination of catecholamine appears to be involved in the progress of neurodegenerative disorders, such as Parkinson disease and via oxidative damage to the mitochondrial membrane and DNA (Hauptmann et al., 1996). Cloning of the cDNAs for MAO A and B demonstrates that these two forms of the enzyme are coded by different genes (Bach et al., 1988) which were derived from the same ancestral gene (Grimsby et al., 1991). Both genes are located on the x chromosome at Xp11.23 to Xp22.1 in tail to tail orientation (Chen et al., 1992). MAO A and B transcripts were detected in most human tissues examined this suggests a functional need to eliminate their substrates (Grimsby et al., 1990).
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However, they do show different tissue and cell distribution. MAO A is predominantly found in catecholaminergic neurons, and MAO B is most abundant in serotonergic and histaminergic neurons and glial cells (Saura et al., 1994). The highest expression of MAO A was in placenta and MAO B is specific in platelets and lymphocytes (Sullivan et al., 1978). Deletion of MAO A activity in males in a Dutch family resulted abnormal aggressiveness (Brunner et al., 1993). Aggressive behavior was also observed in MAO A deficient mice (Cases et al., 1995) and not observed in MAO B knock out mice (Grimsby et al., 1997; Shih et al., 1999). A new function of MAO that is related to imidazole binding has recently been suggested (Raddatz et al., 1995). The cell and tissue specific expression of MAO is encoded within the gene and the promoter. The DNA sequence of the promoter contents the binding motif for different transcription factors which interacts with transcription machinery and determines the level of gene expression. This review will discuss the promoter organization of human MAO A and B and their expression in the cell lines selected for study. Entrez-PubMed database search was based on the following keywords: monoamine oxidase, promoter, and gene expression.
IDENTIFICATION OF HUMAN MAO A AND B GENE CORE PROMOTERS Using a series of 50 flanking sequences linked to a human growth hormone reporter gene, the DNA sequence responsible for the transcription activation of MAO A and B genes were identified. When these constructs were transfected into NIH3T3, SHSY-5Y, and COS 7 cells, the maximal promoter activity for MAO A and B was found in a 0.14 kb PvuII/DraII and 0.15 kb PstI/NaeI fragment, respectively (Zhu et al., 1992). Both fragments are GC rich, contain potential Sp1 binding sites, and share approximately 60% sequence identity. However, the organization of the transcription elements is distinctly different between these two promoters. The MAO A 0.14 kb fragment lacks a TATA box, consists of three Sp1 elements (Yoshida et al., 2002) (Denney et al., 1994), and exhibits bi-directional promoter activity (Zhu et al., 1994). Additional Sp1 sites, CACCC elements, CCAAT boxes, and four 30 bp direct repeats are found in fartherupstream sequences in MAO A core promoter (Zhu and Shih, 1997). MAO B core promoter 0.15 kb fragment consists of two clusters of overlapping Sp1 sites separated by a CACCC element. The different promoter
organization of MAO A and B genes may underlie their different tissue- and cell-specific expression (Zhu et al., 1992). The MAO B core promoter constructs was used to test the ethanol treatment of SHSY-5Y neuroblastoma cells and MG1242 glioma cells. An increase of 2–3fold reporter gene expression and enzyme activity were observed after ethanol treatment of transfected cells. Gel retardation analysis with B0.15 fragment showed that ethanol caused changes in transcription factor binding to the MAO B core promoter in both cell lines in a cell-type specific fashion (Ekblom et al., 1996). The same B0.15 fragment was used to perform gel shift assays using nuclear extracts from human brain and lymphocytes. The binding patterns of two uncharacterized transcription factors were correlated between monoamine oxidase B enzyme activity in platelets (Ekblom et al., 1998). It will be interesting to characterize these unknown factors to understand the significance.
DIFFERENT REPORTER SYSTEM MAY RESULT IN DIFFERENT MAO A PROMOTER ACTIVITY MAO A-luciferase reporter constructs that contained all the known transcription initiation sites exhibited no evidence for inhibitory cis-elements between 200 and at least 935. The apparent inhibitory activity previously reported for sequences 50 to the most proximal PvuII site may have resulted from the use of partial promoter constructs that omitted the putative Inr element located between 30 and 40 bp 50 to the ATG codon (Denney et al., 1994). In MAO A-human growth hormone reporter constructs with or without the Inrlike sequence, the promoter activity decreases significantly in the cell lines tested. These results suggest that although the Inr-like sequence is present in the human MAO A promote, it acts as a negative cis-element instead of a transcription initiator (Zhu and Shih, 1997). The human growth hormone reporter system may also have some unknown elements within the vector sequence which is not a popular reporter system compare with dual-luciferase system.
A FUNCTIONAL POLYMORPHISM IN THE MAO A GENE PROMOTER An extensive repeat structure contained in two 90 bp repeats was present in the MAO A promoter sequence
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which down-regulates human MAO A promoter activity (Zhu and Shih, 1997). This polymorphism located 1.2 kb upstream of the MAO A coding sequences, consists of a 30 bp repeated sequence present in 3, 3.5, 4 or 5 copies in from different individuals across ethnic groups. The polymorphism has been shown to affect the transcriptional activity of the MAO A gene promoter in an luciferase assay system. Alleles with 3.5 or 4 copies of the repeat sequence are transcribed 2–10 times more efficiently than those with 3 or 5 copies of the repeat, suggesting an optimal length for the regulatory region (Sabol et al., 1998). This functional association of MAO A promoter activity and polymorphism became a useful genetic marker for PCR based analysis using genomic DNA from human population of behavior interests. These include aggression (Manuck et al., 2000), alcoholism (Koller et al., 2003; Lu et al., 2002; Parsian et al., 2003; Saito et al., 2002), antisocial alcoholism (Samochowiec et al., 1999), antisocial and anxious-depressive alcoholics (Schmidt et al., 2000), attention deficit (Lawson et al., 2003), attention deficit hyperactivity disorder (Manor et al., 2002), autism (Yirmiya et al., 2002), bipolar affective disorder (Furlong et al., 1999; Ho et al., 2000; Kirov et al., 1999), idiopathic generalized epilepsy (Haug et al., 2000), depression (Muller et al., 2002), major depressive disorder (Yoshida et al., 2002), mood disorder (Kunugi et al., 1999), panic disorder (Hamilton et al., 2000; Norton et al., 1999; Sand et al., 2000), restless legs syndrome (Desautels et al., 2002), schizophrenia (Norton et al., 2002), smoking (Ito et al., 2003), and psychiatric disorders (Syagailo et al., 2001). The number of publication is still increasing and conflicting results is very common because most of the sample in the studies listed is small and the human behavior analyzed involves multiple genes, MAO A is just one of the gene involved (Williams et al., 2003). More detailed understanding on the transcription factors involved in the 2 kb MAO A promoter is necessary before more answer can be obtained. The MAO A promoter tandem repeat region has been associated with the MAO A activity in human male skin fibroblasts. The median MAO A activity in cultures with three repeats was significantly lower than that in cultures with four repeats (Denney et al., 1999). This is consistent with published evidence that MAO A promoter constructs bearing three repeats have lower transcriptional activity in transfected neuroblastoma and choriocarcinoma cells (Sabol et al., 1998). The promoter tandem repeat may also participate differentially in the regulation of dopamine and serotonin turnover rates under presumed steady state in the
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central nervous system (Jonsson et al., 2000). However, no association of the variants and the resulting haplotypes with expression levels and enzyme activities of MAO A in human cortical brain autopsies (Balciuniene et al., 2002). Despite all the conflicting results surrounding the MAO A promoter polymorphism, a hypothesis was proposed that the effect of MAO A gene would be more readily revealed if the environment were explicitly taken into account. A large sample of male children from birth to adulthood was followed for 26 years to determine why some children who are maltreated grow up to develop antisocial behavior, whereas others do not. Although the MAO A genotype by itself was not correlated with antisocial behavior, the individuals with both a low-MAO A activity genotype and previous maltreatment were by far the most likely to have committed a violent crime and to be diagnosed with conduct disorder (Caspi et al., 2002). Hopefully more cohorts will be available to verify this finding. All these associated studies is base on the assumption that the brain MAO A enzymatic activity might be associated with human neuropsychiatric disorders and behavioral traits (Shih and Thompson, 1999). It is known that MAO A activity levels are highly variable among humans. Up to 100-fold (Castro Costa et al., 1980) and 515-fold (Denney et al., 1999) differences in MAO A activity have been detected in cultured skin fibroblasts which is the only non-invasive method to obtain the MAO A enzymatic activity for human. It has been proposed that the individual variation of MAO A activity levels is determined by genetic components (Hotamisligil and Breakefield, 1991), but our knowledge about the regulation of MAO A activity in human brain is still limited simply because the samples are not readily available. The cell culture system is still the only method which will help us to understand the molecular mechanism regulating the MAO A expression.
REGULATION OF HUMAN MAO B GENE BY Sp1 AND Sp3 As previously showed that the 246/99 MAO B promoter region exhibited the highest activity and contained two clusters of overlapping Sp1 sites, a CACCC element and a TATA box. Analysis of nine site-directed mutations of 246/99 region reveals that both clusters of Sp1 sites contribute positively whereas the CACCC element contributes negatively to the transcriptional activity. Gel shift analysis demonstrates that in addition to Sp1, Sp3 can interact with
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both clusters of Sp1 sites. Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2. These results suggest that the binding to the overlapping Sp1 sites by various members of Sp family is important for the regulation of the MAO B gene expression in human astrocytoma (MG1242) and hepatocytoma (HepG2) and cervical adenocarcinoma (HeLa) cell lines (Wong et al., 2001). Additional potential regulatory elements, including AP1, AP4, CAAT, GATA, upstream stimulatory factor (USF), estrogen receptor (ER), and sex-determining region Y-box5 (Sox5) were identified within the 2 kb 50 flanking sequence. The function of these potential elements will be tested when appropriate cell lines become available.
ACTIVATION OF HUMAN MAO B GENE BY A PROTEIN KINASE C MAPK SIGNAL TRANSDUCTION PATHWAY Phorbol-12-myristate-13-acetate (PMA) increases human MAO B but not MAO A gene expression. The sequence between 246 and 225 bp consists of overlapping binding sites (Sp1/Egr-1/Sp1) that are recognized by Sp1, Sp3, and PMA-inducible Egr-1 is essential for PMA activation. PMA transiently increases Egr-1 and c-jun gene expression. Site directed mutations show that Egr-1 and c-Jun transactivate the MAO B promoter and increase endogenous MAO B transcripts via the Sp1/Egr-1/Sp1 overlapping binding sites. Sp3 inhibits Sp1 and Egr-1 activation of MAO B gene expression. c-fos gene expression was increased by PMA but not involved in MAO B gene transcription. Furthermore, protein kinase C inhibitor blocks the PMA dependent activation of MAO B. Cotransfection of the MAO B promoter with dominant negative forms of Ras, Raf-1, MEKK1, MEK1, MEK3, MEK7, ERK2, JNK1, and p38/RK inhibit the PMA dependent activation of the MAO B promoter. These results indicate that MAO B expression is selectively induced by the activation of protein kinase C and MAPK signaling pathway and that c-Jun and Egr-1 appear to be the ultimate targets of this regulation in HepG2 cell line (Wong et al., 2002). The Sp1/Egr-1/Sp1 overlapping binding sites has been used as a bait in a yeast one-hybrid vector to screen an expression library. Many positive clones were obtained. One of
them contain Zinc finger binding motif and nuclear localization signals. This protein may belong to a new Sp1-like protein family (Cook et al., 1999). The function of this protein and its influence on MAO B is under investigation.
STEROID HORMONES INFLUENCE MAO ENZYMATIC ACTIVITY In human skin fibroblasts, the original undetectable MAO A enzymatic activity can be elevated to detectable level by dexamethasone treatment (Edelstein and Breakefield, 1986). Careful examine the 2 kb MAO A promoter region reveals three potential glucocorticoid response elements. It is important to identified the function of these elements because the hormonal influence of MAO enzymatic activity will certainly alter the concentration of neurotransmitters in the brain which may change the mental status. The glucocorticoid response has also been reported in MAO B in cultured rat astrocytes (Carlo et al., 1996). The MAO B activity increases by retinoic acid treatment in cultured chicken hepatocytes has also been reported (Nicotra et al., 2002). There is a 20-fold difference in MAO A expression between androgen dependent and independent prostate cancer LNCaP cell lines (Vaarala et al., 2000). The expression of MAO in female will be interesting because there are two X-chromosomes present in females. Additional regulation on the promoter involving X-chromosome inactivation will increase the complexity for analysis. As mentioned earlier, the potential estrogen receptor binding site has been identified within the 2 kb MAO B promoter region. The proper cell lines of female origin will be discovered to demonstrate the function of this potential binding element.
SUMMARY AND FUTURE PROSPECTIVE In the preceding sections, the current knowledge on MAO A and B promoter has been reviewed. The Sp1 family transcription factors were identified to be the major players regulating both MAO A and B promoters. However, the information encoded within the MAO genes should content all the blueprints for their temporal and special expression pattern within the proper cell lineage, the ability to response to the physiological changes such as hormones, glucose concentration, neurotransmitters, oxygen tension, temperature, etc. These complex signal interactions can be
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accomplished through different signal transduction pathway via protein–protein, protein–DNA interactions, and protein modification and intracellular translocation. There are a lot of work need to be accomplished before we can have satisfactory answer to the molecular mechanism of tissue specific expression of MAOs.
ACKNOWLEDGEMENTS The author would like to thank Jean C. Shih for support and encouragements.
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