Endocrine Journal 2007, 54 (5), 659–666

REVIEW

Roles and Regulation of MafA in Islet β-cells

SHINSAKU ARAMATA, SONG-IEE HAN* AND KOHSUKE KATAOKA

Graduate School of Biological Science, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan *Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8572, Japan

Abstract. is a critical hormone in the regulation of blood glucose levels. It is produced exclusively by pancreatic islet β-cells. β-cell-enriched transcription factors, such as Pdx1 and Beta2, have dual roles in the activation of the insulin promoter establishing β-cell-specific insulin expression, and in the regulation of β-cell differentiation. It was shown that MafA, a β-cell-specific member of the Maf family of transcription factors, binds to the conserved C1/RIPE3b element of the insulin promoter. The Maf family regulate tissue-specific and cell differentiation in a wide variety of tissues. MafA acts synergistically with Pdx1 and Beta2 to activate the insulin gene promoter, and mice with a targeted deletion of mafA develop age-dependent diabetes. MafA also regulates involved in β-cell function such as Glucose transporter 2, Glucagons-like peptide 1 receptor, and Prohormone convertase 1/3. The abundance of MafA in β- cells is regulated at both the transcriptional and post-translational levels by glucose and oxidative stress. This review summarizes recent progress in determining the functions and roles of MafA in the regulation of insulin gene transcription in β-cells.

Key words: Insulin, Transcriptional regulation, Glucose response, Glucotoxicity, Diabetes (Endocrine Journal 54: 659–666, 2007)

Transcriptional regulators of element of the insulin promoter as a heterodimer with insulin gene expression the ubiquitous bHLH factor E47. Both Pdx1 and Beta2 are expressed in islet endocrine cells, and gene Insulin is a polypeptide hormone that is critical in ablation experiments in mice have demonstrated that the regulation of blood glucose levels. It is produced these proteins play critical roles in insulin gene expres- exclusively by β-cells in the islets of Langerhans in the sion, as well as in islet development and function. In pancreas. A region of approximately 350 base pairs humans, Pdx1 and Beta2 are responsible for the matu- (bp) of the insulin promoter are sufficient to direct β- rity-onset diabetes of the young (MODY) type 4 and 6, cell specific expression of insulin, and within this respectively, and mutations in these proteins have also region, functionally important cis-regulatory elements been identified in some cases of type 2 diabetes melli- and trans-acting factors have been identified (Fig. 1) tus. Genes responsible for other types of MODY, such (for review, see [1]). as HNF1α (MODY3), HNF1β (MODY5), and HNF4α Pdx1 is a homeodomain-containing transcription (MODY1), have also been shown to regulate insulin factor, and binds several elements in the insulin pro- gene expression either directly by binding to the pro- moter: A1, GG2, and A3. Beta2 is a basic helix-loop- moter, or indirectly by regulating other insulin tran- helix (bHLH) transcription factor, and binds to the E1 scription factors. The C1 (in human) or RIPE3b (in rat) element of Correspondence to: Kohsuke KATAOKA, Graduate School of the insulin promoter also plays a critical role in β-cell- Biological Science, Nara Institute of Science and Technology, specific insulin gene expression, as well as in glucose- 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan regulated insulin expression [2]. A β-cell-restricted 660 ARAMATA et al.

Fig. 1. Key regulators of the insulin gene promoter. Important cis-elements and trans-factors required for β-cell-specific insulin gene expression are shown. MODY: maturity- onset diabetes of the young. Type2DM: type2 diabetes mellitus.

C1-binding factor was identified that appears in re- sponse to glucose in pancreatic β-cell nuclear extracts [3]. Recently, MafA, a member of the Maf family of transcription factors, was identified as the C1-binding factor of the earlier study [4–7]. This review will fo- cus in the functions and roles of MafA.

Characteristics of Maf transcription factors

The Maf family of transcription factors is a sub- group of the basic leucine zipper (bZip) family of tran- scription factors. Maf proteins are homologous to the viral Maf (v-Maf) oncoprotein, the original member of the Maf family, which was identified as the transform- ing element in the genome of the AS42 chicken mus- culoaponeurotic fibrosarcoma retrovirus in 1989 [8]. To date, genes encoding Maf family proteins have been isolated from vertebrate (mammals, birds, frogs, and fish) and from invertebrate (Drosophila) species (summarized in [9]). Maf family members are unique among bZip factors in that they contain a highly con- served extended homology region (EHR), or ancillary DNA binding region, in addition to a typical basic re- Fig. 2. Structures and DNA recognition sequences of Maf fam- gion, and both regions are involved in target DNA se- ily transcription factors. quence recognition (Fig. 2). Schematic representation of the structures of human The members of the Maf family of proteins are sub- (MafA, MafB, c-Maf and Nrl) and chicken (L-Maf) large Maf factors and their amino acid identities (%) with divided into two groups, large Maf and small Maf pro- MafA are shown. MARE: Maf-recognition element. teins, based on their structures and functions. MafA belongs to the large Maf group, which also in- cludes MafB, c-Maf, and Nrl in mammals (Fig. 2). L- Maf proteins have a conserved amino-terminal domain Maf is the chicken counterpart of MafA. The large involved in their transactivator function. This domain INSULIN TRANSCRIPTION AND MafA 661 is rich in Asp (D), Glu (E), Ser (S), Thr (T) and Pro (P) role in cell differentiation during development. For residues, and recent findings suggest that phosphoryla- example, L-Maf (the chicken counterpart of mamma- tion within this domain regulates the biological activi- lian MafA) was identified as a transcription factor ty of Maf proteins [10, 11] (see below). The region which binds to the lens-specific enhancer of the chick- between the D/E/S/T/P-rich domain and the bZip do- en αA-crystallin gene [16]. L-Maf also activates other main is relatively divergent among the family mem- crystallin genes, including chicken βB1- and δ1-crys- bers and is referred to as the hinge region. With the tallin, by binding to MARE sequences located in the exception of Nrl, this region contains stretches of poly promoter or enhancer regions of these genes [16]. glycine or poly histidine, which can form a flexible Gain- or loss-of-function experiments in the develop- hinge in the protein. ing chick embryo revealed that L-Maf is a key regula- The large Maf proteins (hereafter referred simply as tor of lens development [16]. Maf proteins) form homodimers through their leucine c-Maf, the cellular counterpart of v-Maf, was redis- zipper domains and bind to consensus DNA sequences covered as a T helper 2 (Th2) lineage-specific gene termed Maf-recognition elements (MAREs) (Fig. 2) product that regulates Th2-specific interleukin-4 ex- [12, 13]. The T-MARE element (TGCTGACTCAG- pression [17]. Nrl, which was isolated as a gene prod- CA) contains a phorbol 12-O-tetradecanoate-13-acetate uct specifically expressed in photoreceptor cells in the (TPA)-responsive element (TRE: TGACTCA) and the retina [18], is a regulator of photoreceptor-specific C-MARE element (TGCTGACGTCAGCA) contains rhodopsin gene expression [19, 20]. Knockout mice a cyclic AMP-responsive element (CRE: TGACGT- have revealed that Nrl is required for the development CA), to which the AP-1 and the CREB/ATF families of rod photoreceptor cells [21], and missense muta- of bZip proteins bind, respectively. In contrast to typi- tions in human nrl are associated with autosomal dom- cal bZip proteins, such as AP-1 (Fos and Jun) and inant retinitis pigmentosa [22]. ATF/CREB family members, Maf proteins bind to mafB was identified as the gene responsible for the relatively long nucleotide sequences (13–14 bp in phenotype of the mouse mutant kreisler, in which or- length). While some base mismatches in the consen- ganization of the 5th and 6th rhombomeres (r5/r6), the sus recognition sequence are allowed in Maf ho- segmental compartments in the developing hindbrain, modimer binding to the palindromic MAREs, GC is abnormal. MafB is expressed in r5/r6 during em- residues flanking the central TRE or CRE seem to be bryogenesis [23] and regulates the expression of hoxa- critical for binding [12, 13]. Recently, Yoshida et al. 3 and hoxb-3 in r5/r6 and r5, respectively, by binding showed that Maf homodimers also bind efficiently to to r5/r6- and r5-specific enhancer elements [24, 25]. a MARE half-site preceded by an AT-rich sequence (AT-rich plus half MARE) (Fig. 2), indicating that AT-rich sequences flanking MAREs are also impor- Roles of MafA, Pdx1, and Beta2 in β-cells tant for binding [14]. Thus, Maf proteins are unique among bZip proteins in that they can bind to several As described above, the C1/RIPE3b element in the types of target sequences, including palindromic insulin gene promoter plays a critical role in β-cell- MAREs and AT-rich plus half MAREs. The DNA- specific and glucose-regulated expression of insulin sequences of regulatory elements of well-characterized [2]. A β-cell-restricted C1-binding factor that ap- Maf target genes are related to these sequences [14, peared in response to glucose in pancreatic β-cell nu- 15]. clear extracts was originally detected by gel mobility shift analysis [3], but at the time, was not molecularly identified. In 2002 and 2003, the C1-binding factor Maf transcription factors as regulators of was purified biochemically and identified as MafA tissue-specific gene expression [4, 6]. Using a bioinformatics approach to search for MARE-related sequences in the GenBank database, Although v-Maf was identified as a retroviral trans- we found that the C1/RIPE3b element is similar to forming protein, it is now widely accepted that Maf MARE and is conserved among species (Fig. 3A). We family proteins are regulators of a wide variety of cell- then isolated MafA as a β-cell restricted member of the and tissue-specific gene expression, and also play a Maf family of proteins, and showed that the C1/ 662 ARAMATA et al.

However, the precise molecular mechanism underly- ing the synergistic activity of MafA, Pdx1, and Beta2 is unknown. From a clinical point of view, it is noteworthy that simultaneous expression of MafA, Pdx1, and Beta2 in non-β-cells, such as liver cells, induced expression of the endogenous insulin gene, as well as other β-cell- specific genes, such as Glucokinase and the potassium channel subunits Kir6.2 and SUR1. These results indi- cate that MafA, Pdx1 and Beta2 are excellent potential targets for gene therapy approaches to the treatment of diabetes [27, 32]. Recently, it was demonstrated that mafA knockout mice develop age-dependent diabetes [26]. At birth, islets of the mafA knockout mice are morphologically normal, but with age, the mice display impaired glu- cose-stimulated insulin secretion (GSIS) and abnormal islet architecture. Expression of insulin, as well as the Glucose transporter 2 (GLUT2), an important compo- nent of the glucose-sensing system in β-cells, is re- duced in the islets of mafA knockout mice. Similar phenotypes have been observed in or beta2 knockout mice. Targeted disruption of pdx1 in mice results in pancreatic agenesis, which precludes further analysis, but mice with β-cell-restricted pdx1 gene ab- lation using cre-loxP system develop diabetes with age Fig. 3. Genes regulated by MafA in β-cells. [33]. They also exhibit impaired glucose tolerance, A. Conserved C1 (human) and RIPE3b (rat) elements of abnormal islet architecture, and reduction of insulin the insulin gene promoter and their similarity to the MARE. B. A list of genes regulated by MafA and their and GLUT2 expression. Mice with targeted ablation functions in β-cells. Asterisks indicate that evidence for of Beta2 exhibit diabetes due to a great reduction of direct interaction of MafA to its promoter or enhancer β-cell number at birth, or a defect in postnatal β-cell region is not reported. neogenesis, depending on their genetic background [34]. Based on these observations, MafA, Pdx1, and RIPE3b element is a target of MafA [5, 12]. Beta2 seem to be involved not only in insulin gene MafA is a weak transactivator of the insulin promoter transcription, but also in proliferation and survival of when expressed alone, as are Pdx1 and Beta2. How- β-cells in the adult pancreas. ever, when these three factors are co-expressed, they Roles of MafA in β-cell functions are also implicat- synergistically and strongly activate the insulin pro- ed by studies of MafA overexpression in β- and non β- moter [26–29]. MafA is expressed in β-cells, but not cell lines [27, 35]. MafA seems to regulate not only in α-, γ- or δ-cells, in adult pancreatic islets [6, 30, 31]. insulin gene expression but also other genes involved In contrast, expression of Pdx1 and Beta2 is not re- in β-cell functions, such as insulin biosynthesis, insu- stricted to β-cells. Therefore, β-cell-restricted expres- lin secretion and glucose (Fig. 3B). These sion of the insulin gene seems to be established by the genes include Prohormone convertase 1/3, potassium synergistic action of these transcription factors. Fur- channel subunits Kir6.2 and SUR1, Glucagon-like thermore, a direct interaction of MafA with both Pdx1 peptide 1 receptor (GLP1-R), GLUT2, Glucokinase and Beta2 has been demonstrated [26]. Generally, and Pyruvate carboxylase. MafA also regulates ex- such protein-protein interactions enhance the affinity pression of other β-cell transcription factors, Pdx1, of trans-factors for their respective cis-elements and/or Beta2 and Nkx6.1. Thus, MafA is a key regulator of co-activators, thus stabilizing DNA-protein complexes. genes implicated in maintaining β-cell function. INSULIN TRANSCRIPTION AND MafA 663

Fig. 4. Multiple modes of MafA regulation in β-cells. Transcription of the mafA gene, as well as MafA protein stability, in β-cells is regulated by acute and chronic exposure to glucose, oxidative stress, and fatty acids. MafA protein is constitutively phosphorylated at multiple sites by GSK3. Phosphorylation is a prerequisite for rapid degradation of MafA under low-glucose conditions.

Regulation of mafA expression and derlying molecular mechanisms of these responses to MafA protein levels in β-cells glucose exposure. As illustrated in Fig. 4, both transcriptional and In pancreatic β-cells, insulin secretion and insulin post-translational processes have been implicated in gene expression are regulated by a variety of extra- the regulation of MafA by acute and chronic glucose cellular stimuli, including glucose, under both physio- exposure of β-cells. Levels of mafA mRNA and MafA logical and pathological conditions. Insulin gene protein are increased under high glucose conditions [5, transcription is stimulated by short-term exposure to 26]. Recently, Kitamura et al. showed that glucose high glucose. However, long-term or chronic expo- and oxidative stress regulate mafA expression at the sure to high glucose, as in hyperglycemia in type 2 transcriptional level through FoxO1, a forkhead tran- diabetes, leads to β-cell dysfunction and decreased in- scription factor involved in oxidative stress responses sulin production. The molecular mechanism of β-cell and metabolism [37]. Raum et al. identified a cis- failure (glucotoxicity) is not well understood, but oxi- regulatory region of mafA approximately 8 kb up- dative stress caused by excess glycolytic reactions may stream of the transcription start site, which regulates play a role. Previously, C1/RIPE3b-binding activity in its β-cell-specific expression [38]. Pdx1, FoxA2, and β-cells, which plays a critical role in the regulation of Nkx2.2, which are all important transcriptional regu- β-cell-specific and glucose-regulated expression of the lators of β-cell formation and function, regulate tran- insulin gene, was shown to increase in response to scription of mafA by binding to this cis-regulatory short-term glucose exposure, and decrease in response region [38]. to chronic glucose exposure or oxidative stress [3, 36]. Harmon et al. have shown that chronic exposure of a As indicated above, MafA was identified as the C1/ β-cell line to high glucose leads to a decrease in MafA RIPE3b-binding factor, providing evidence of the un- protein without a corresponding change in mafA 664 ARAMATA et al. mRNA level, indicating a post-translational mecha- cells (lipotoxicity), including defects in glucose-induced nism of control of MafA protein stability by oxidative insulin secretion and insulin transcription. The molec- stress [39]. Lawrence et al. have reported that MafA ular mechanisms underlying lipotoxicity are unknown, forms a complex with the NFAT transcription factor but recently it was shown that exposure of β-cells to on the insulin promoter and activates transcription in palmitate decreases insulin expression through reduc- response to high glucose stimuli. Under chronic glu- tion of mafA mRNA expression, as well as nuclear ex- cose exposure, MafA is replaced by C/EBPβ, which clusion of Pdx1 [43]. negatively regulates the insulin promoter [40]. Based on these findings, MafA abundance in β-cells Recently, we found that MafA is constitutively appears to be regulated by various extracellular stimuli phosphorylated at multiple serine and threonine resi- at multiple levels, including transcription and protein dues in the amino-terminal region (Fig. 4) [41]. Ser65 stability. MafA activity as transcriptional activator of MafA is first phosphorylated by an unidentified may also be regulated by post-translational modifica- kinase (priming kinase), and then glycogen synthase tions such as phosphorylation. kinase 3 (GSK3) sequentially phosphorylates Ser61, Thr57, Thr53 and Ser49. We have also shown that MafA protein is degraded by the proteasome in low Conclusion and future prospects glucose conditions, and multiple phosphorylation at these residues is a prerequisite for degradation. The Investigations into the molecular mechanisms of molecular mechanism by which phosphorylated MafA gene regulation by MafA have recently emerged. Elu- undergoes rapid degradation in response to low glu- cidation of MafA regulation in β-cells will enable us to cose is still unknown. Recently, Vanderford et al. develop a comprehensive understanding of the patho- showed that MafA induction by glucose is mediated physiology of β-cells and the molecular mechanisms by hexosamine biosynthetic pathway [42]. Therefore, of glucotoxicity and lipotoxicity. It will also inform O-GlcNAc modification of MafA and/or proteasome the development of efficient gene therapy applications subunits may be involved in the regulation of MafA in the area of β-cell neogenesis, β-cell transdifferentia- protein abundance. tion, or β-cell generation from ES cells, for the cure of In obesity, or in type 2 diabetes, prolonged exposure diabetes. of β-cells to fatty acids also causes dysfunction of β-

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