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Biochimica et Biophysica Acta 1823 (2012) 1841–1846

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Biochimica et Biophysica Acta

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Review The transcription factors MAFF, MAFG and MAFK: Current knowledge and perspectives

Meenakshi B. Kannan a,b, Vera Solovieva a,b, Volker Blank a,b,c,⁎

a Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada b Department of Medicine, McGill University, Montreal, QC, Canada c Department of Physiology, McGill University, Montreal, QC, Canada

article info abstract

Article history: The small MAFs, MAFF, MAFG and MAFK have emerged as crucial regulators of mammalian expression. Received 27 February 2012 Previous studies have linked small MAF function, by virtue of their heterodimerization with the Cap ‘n’ Collar Received in revised form 11 June 2012 (CNC) family of transcription factors, to the stress response and detoxification pathways. Recent analyses Accepted 12 June 2012 have revealed a complex regulatory network involving small MAF transcription factors and other cellular Available online 18 June 2012 . The expression and activity of small MAFs are tightly regulated at multiple levels. With regard to their clinical importance, small MAFs have been linked to various diseases, such as diabetes, neuronal disorders, Keywords: MAF thrombocytopenia and carcinogenesis. A better understanding of the molecular mechanisms governing the bZIP activity of small MAFs will provide novel insights into the control of mammalian transcription and may lead to CNC the development of novel therapeutic strategies to treat common human disorders. Gene regulation © 2012 Elsevier B.V. All rights reserved. Stress signaling Cancer

1. Introduction of tissues, albeit at various levels [15–18]. Despite the lack of an evident transactivation domain, the small MAFs have emerged as important The advent of the MAF (proto-) oncogene family began with the dis- transcriptional regulators [19]. covery of the founding member, the oncogene v-Maf, which was identi- A series of comprehensive articles on MAF proteins has covered var- fied during the analysis of the avian transforming retrovirus isolated ious aspects of the biology of these intriguing transcriptional regulators from chicken musculoaponeurotic fibrosarcoma (Maf) [1]. The MAFs [3–5,19–22]. The present review serves as an update, describing new are members of the basic (bZIP) family of transcription insights into the regulation and function of small MAF transcription factors, which also includes AP-1, CREB/ATF, CNC, C/EBP and PAR factors as well as their roles in disease pathology. proteins [2]. The MAF proteins, like other members of the bZIP family, possess 2. Multifaceted small MAF regulatory networks evolutionary conserved basic and leucine zipper domains. The basic domain binds DNA, whereas the leucine zipper mediates homo- or Small MAF proteins form heterodimers with members of the Cap ‘n’ hetero-dimerization with specific bZIP transcription factors. MAF family Collar (CNC) family that includes NFE2 [nuclear fac- members can be divided into two groups, small and large MAF proteins. tor (erythroid-derived 2), 45 kDa], NFE2L1 [nuclear factor (erythroid- The large MAFs, including C-MAF, MAFA/L-MAF, MAFB/KREISLER and derived 2)-like 1, also known as NRF1], NFE2L2 (NRF2), NFE2L3 NRL proteins, contain an acidic N-terminal transactivation domain and (NRF3) and the more distantly related BACH1 and BACH2. In addition, play key roles in mammalian gene regulation, cellular differentiation the small MAFs have been shown to interact with several different pro- and oncogenesis [3–5]. The small MAFs, MAFF, MAFK and MAFG are teins (Table 1) resulting in a complex interactome [19,20]. The small highly homologous proteins of about 18 kDa in molecular weight MAFs can also homodimerize and act, especially upon overexpression, [6,7], and are localized predominantly in the nucleus [8–10]. The small as transcriptional repressors [21,23]. Small MAFs, heterodimerizing MAFs display a complex expression pattern during embryogenesis with other bZIP transcription factors, can act either as transcriptional [11–14]. In adult mice, the small MAFs are expressed in a wide variety activators or repressors depending on their dimerization partners [19]. The members of the CNC family of transcription factors, which lack the capacity to bind DNA on their own, require small MAFs as oblig- ⁎ Corresponding author at: Lady Davis Institute for Medical Research, Department of atory dimerization partners for their function as transcriptional regu- Medicine, McGill University, 3755 Cote Sainte-Catherine Rd, Montreal, Quebec, Canada H3T 1E2. Tel.: +1 514 340 8260x4984. lators. The MAF recognition element (MARE) sequence typically E-mail address: [email protected] (V. Blank). comprises TPA-responsive element (TRE) or cyclic AMP-responsive

0167-4889/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.bbamcr.2012.06.012 1842 M.B. Kannan et al. / Biochimica et Biophysica Acta 1823 (2012) 1841–1846

Table 1 on the respective levels of the CNC and small MAF proteins within the Interactome of small MAF proteins. cell [21,26]. Using in vivo models, it has also been shown that positive Interaction with small MAF References or negative MARE-dependent transcriptional regulation is dependent on the abundance of small MAF proteins [27]. Based on studies from Leucine zipper proteins – MAFF + [69] various laboratories [3,4,19 22], a model of the cellular network of MAFG + [69] small MAF transcription factors is shown (Fig. 1). MAFK + [69] Recent studies shed light on additional components of the cellular NFE2 P45 + [15,69,70] functions of small MAF proteins. MAFG has been shown to regulate NFE2L1 + [15,70–72] NFE2L2 + [15,69,70,72–74] the intracellular localization of NFE2L2, thereby controlling its tran- NFE2L3 + [75,76] scriptional activity. Heterodimerization with MAFG increased the BACH1 + [77] nuclear retention of NFE2L2, by masking the nuclear export signal BACH2 + [77] (NES) located in the bZIP domain of NFE2L2, thus rendering it inacces- FOS + [69] sible to the nuclear exporting protein, region maintenance FOSB + [78] MIP + [79] 1 (CRM1) [28]. Since NFE2L2 is a protein with a rapid turnover, it was v-MAF − [80] proposed that heterodimerization with MAFG leads to its stabilization MAFB − [80] by promoting cytosolic exclusion and nuclear accumulation. − JUN [70] Newer data also link small MAFs to the hypoxic response. MAFG has

Other proteins been found to interact with hypoxia inducible factor 1, alpha subunit HOX12 + [81] (HIF1A), a key transcription factor involved in the hypoxic response and MHOX/PRX1/PHOX1/PMX1 + [81] a member of the basic helix–loop–helix–per/ARNT/Sim (bHLH-PAS) PAX6 + [81] family. Physical interaction between MAFG and one of the two PAS HIF1A + [29] domains, PAS-A, of HIF1A has been shown by using a yeast two- MATIIA + [32] hybrid assay and confirmed by surface plasmon resonance. MAFG knockdown attenuated nuclear accumulation of HIF1A and repressed element (CRE) [24] core motifs that also serve as target sequences of its hypoxic response. Knockdown of MAFG also led to a significant AP-1 and CREB/ATF families of transcription factors. This overlap in decrease in the transcript levels of erythropoietin, a known HIF1A target the binding motifs leads to complexity in the elucidation of small MAF gene, upon induction of hypoxia in Hep3B cells [29].Ofnote,gene function. In addition, a GC flanking element outside this core sequence expression profiling using ATDC5 chondrocyte cells revealed also an has been found to be important for the binding of small MAFs. Two upregulation of MAFF transcripts under hypoxic conditions [30]. residues in the basic region, directly interacting with the extended GC New data have also revealed a connection between small MAFs bases, have recently been shown to play a crucial role in MAF-specific and methionine adenosyltransferase II A (MATIIA), an enzyme that is DNA recognition [25]. The transcriptional activity is highly dependent required for the catalysis of the methyl donor S-adenosylmethionine.

Fig. 1. Cellular functions of small MAFs. Small MAFs, which are induced in response to cellular stress, are able to homodimerize or heterodimerize with CNC transcription factors and other proteins. They bind to specific recognition sites and control the involved in various cellular processes. Small MAFs are post-translationally modified by acetylation or sumoylation, which have been shown to regulate their transcriptional activity. M.B. Kannan et al. / Biochimica et Biophysica Acta 1823 (2012) 1841–1846 1843

It has been previously shown that heme oxygenase-1(HMOX1) is mod- 4. Role of small MAF proteins in detoxification ulated by MAFK [31], and a recent proteomics study found that MATIIA is recruited to the HMOX1 gene in X63/0 and Hepa1 cells and Cellular studies have revealed links between small MAF proteins and revealed a physical interaction between MAFK and MATIIA. The knock- stress response/detoxification pathways. Small MAF homodimers and down of MATIIA resulted in derepression of HMOX1. Since MAFK has CNC/small MAF heterodimers recognize MARE sequences, which re- been previously shown to modulate HMOX1 , it is semble the antioxidant response element (ARE) found in the regulatory proposed that MATIIA could act as a corepressor of MAFK, together reg- regions of many phase II drug-metabolizing enzyme and antioxidant ulating the mRNA and protein levels of HMOX1 [32]. MAFG has also genes [19,20,40,41]. Single and compound small MAF knockout mouse been linked to MATIIA, as this small MAF protein can induce MATIIA models have been generated and their phenotype has been discussed via insulin growth factor-1 (IGF1). Knockdown of MAFG lowered basal previously [19,20]. Mice lacking all three small MAF proteins have MATIIA levels and reduced IGF-1 mediated induction of MATIIA [33]. been shown to be embryonic lethal and genechip expression array anal- Novel studies also implicated MAFK in impaired erythroid matura- ysis of mouse embryonic fibroblasts (MEF) generated from these mice tion mediated by the 89 kDa zinc finger protein (ZBP-89). ZBP-89 has showed that small MAF proteins are essential for the activation of been reported to have a direct role in the regulation of human globin genes involved in stress response and detoxification [41]. A recent and other erythroid-specific gene expression. Lower ZBP-89 levels are follow-up study reported that the triple knockout embryos that lack associated with lower globin and erythroid-specific gene expression, the three small MAFs develop normally until embryonic day E9.5, but and were linked to impaired erythroid maturation [34]. Interestingly, subsequently display growth retardation and liver hypoplasia and die an earlier quantitative proteomic analysis had shown physical inter- approximately at E13.5. The transcript levels of cytoprotective genes action between ZBP-89 and the MAFK/NFE2 heterodimer during the were normal in E10.5 triple knockout embryos, but a significant reduc- induction of mouse erythroleukemia (MEL) cell differentiation [9]. tion in the expression of these genes was observed in the fetal liver at In the animal biology field, a recent study showed a link between E13.5 combined with enhanced apoptosis of hepatocytes and erythroid MAFG and the regulation of HMOX1 in hibernating mammals. Hiber- cells [42]. This study demonstrates the significance of small MAFs post nation comprises long periods of deep torpor interspersed by short E9.5 during embryogenesis and further supports the previous cellular periods of arousal, during which an efficient antioxidant defense mech- studies showing that small MAFs mediate stress response and detoxifi- anism is required to defend against the high levels of reactive oxygen cation via AREs. species (ROS) generated. HMOX1 is increased at both transcript and protein levels in the tissues of hibernating ground squirrels. Of interest, 5. Emerging roles of small MAFs in pathogenesis of increased levels of NFE2L2 and MAFG were reported in various organs human diseases of hibernating mammals [35]. Further analyses in hibernating ground squirrels revealed an increase of MAFG protein in brown adipose tissue, Although small MAFs have been associated with the cellular stress liver, heart and lungs, along with increased nuclear accumulation of response, little is known about their specific roles in human health MAFG in liver cells [36]. These data suggest a role for this small MAF and pathology. However, a few studies suggest relevant links be- protein in the induction of HMOX1 during mammalian hibernation. tween small MAFs and various disease pathologies including diabetes, neurological diseases, thrombocytopenia and cancer (Table 2).

3. Posttranslational modifications controlling small MAF activity 6. Potential role for small MAFs in diabetes

A series of studies revealed that small MAFs are regulated by post- A role for small MAFs in the pathology of diabetes has recently translational modifications. The cAMP-response element-binding been revealed based on studies using cellular and transgenic mouse protein (CREB)-binding protein (CBP) has previously been shown to models. MAFA, a member of the large MAF family, has previously acetylate MAFG in erythroid cells. Acetylation of MAFG was shown to been shown to be involved in insulin gene transcription and pancre- enhance the transcriptional activity of the NFE2/MAFG heterodimer atic beta cell function [43–46]. Mice that lack Mafa (Mafa−/−) devel- and augment its DNA binding activity, suggesting that acetylation of op diabetes mellitus (DM) due to impaired insulin gene transcription MAFG plays a vital role in transcriptional control [37]. The p65 subunit and defective pancreatic islets [47]. Transgenic mice that overexpress of NFKB transcription factor has been shown to regulate gene expres- MAFK specifically in their beta cells (Mafk+) develop hyperglycemia sion through the recruitment of specific coactivators such as CBP or at a young age, but they do not develop DM, possibly due to an increase corepressors like histone deacetylases. NFKB p65 has recently been of MAFA DNA binding activity in these mice that may compensate for shown to repress the NFE2L2–ARE pathway, which has an established the overexpression of MAFK. To evade this possible functional redun- role in inflammation and cancer, by two different mechanisms. Firstly, dancy, transgenic Mafa−/− mice overexpressing MAFK specifically in NFKB p65 specifically inhibits the binding of CBP, the principal their beta cells (Mafa−/−Mafk+) were generated [48]. Mafa−/−Mafk+ coactivator of NFE2L2, thereby inhibiting the NFE2L2–ARE pathway. mice, both male and female, developed DM at 5 weeks of age and Secondly, NFKB p65 was found to promote MAFK-associated HDAC displayed a more severe phenotype when compared to the Mafa−/− recruitment to the ARE locus of the HMOX1 enhancer. This enhanced mice. The Mafa−/−Mafk+ mice manifested persistent hyperglycemia HDAC recruitment promotes deacetylation of MAFK and CBP, which and other histological features that are typical characteristics of antagonizes MAFK co-transcriptional activity and also abolishes CBP human diabetic nephropathy [48]. In this context, MAFK is believed to coactivator function [38]. This study reveals a novel link between act as a dominant negative protein antagonizing large MAF protein MAFK acetylation status and NFKB p65-mediated NFE2L2–ARE tran- function in pancreatic beta cells. Hence, MAFK overexpression enhances scriptional control. the diabetic phenotype of Mafa−/− animals and Mafa−/−Mafk+ mice Sumoylationisanotherproteinmodification that has previously may thus serve as a valuable mouse model to investigate diabetic been found to be involved in the control of small MAF activity. It has pathogenesis. been shown that MAFG is conjugated to SUMO-2/3 both in vivo and Reduced levels and dysfunction of endothelial progenitor cells in mouse bone marrow cells. Sumoylation is required for the repressor (EPC) are known features of type-1 diabetes mellitus (DM1) [49]. activity of MAFG and this modification counteracts transcriptional acti- Profiling of EPC gene expression in DM1 patients revealed the down- vation mediated by the NFE2–MAFG heterodimer [39]. Whether the regulation of MAFF, linking this transcription factor to DM1 pathology. other small MAF proteins are controlled by sumoylation is yet to be Interestingly, folic acid supplementation, which serves to the benefit brought to light. of DM1 patients by restoring endothelial cell function, also restored 1844 M.B. Kannan et al. / Biochimica et Biophysica Acta 1823 (2012) 1841–1846

Table 2 Association of small MAFs with disease pathologies.

Disease phenotype Small Maf Observation Reference

Diabetes mellitus type 1 MAFF ∙ Downregulated in DM1 patients [50] MAFK ∙ Overexpression in beta cells causes hyperglycemia [48] ∙ Mafa−/− overexpressing MAFK in beta cells develop severe DM Neuronal disease MAFG & MAFK ∙ Mafg−/−Mafk+/− mice develop progressive motor disorder [53] MAFF ∙ Induced in Parkinson's disease patients by L-Sulforaphane [56] Thrombocytopenia MAFG ∙ Mafg−/− mice develop thrombocytopenia [57] ∙ MAFG expression is suppressed by human interferon (IFN)-alpha leading to thrombocytopenia [61] MAFG & MAFK ∙ Mafg−/− Mafk+/− mice develop severe thrombocytopenia [57] Cancer MAFG ∙ MAFG expression levels are lower in smokers with lung cancer than in smokers without cancer or non-smokers [64] ∙ Mir-218-mediated MAFG levels modulate the airway epithelial gene expression response to cigarette smoke, [65] with a potential relevance to lung cancer phenotype [33] ∙ MAFG expression is induced by insulin-like growth factor-1 (IGF-1) in human colon cancers MAFK ∙ Altered expression in specific acute myeloid leukemia cytogenetic group [67] MAFF ∙ Lower in acute lymphoblastic lymphoma (ALL) patients with translocation t(12;21) [68] ∙ MAFF is downregulated in diverse tumor types [55]

normal MAFF gene expression levels [50]; however, the mechanism un- heterozygous for Mafk develop a more severe phenotype of thrombo- derlying this normalization has yet to be investigated. cytopenia than single knockout Nfe2−/− mice [57]. MAFG expression was found to be downregulated in transgenic mice lacking the 7. Linking small MAFs to neuronal diseases carboxy-terminal regulatory domain of Fli1 (Friend leukemia integra- tion 1) gene. These homozygous Fli1 mutant mice exhibit reduced Small MAFs have also been associated with specific neuronal pheno- viability, reduction in platelet levels, impaired platelet aggregation types. MAFK was shown to be upregulated in PC12 pheochromocytoma and prolonged bleeding, suggesting a role for MAFG in megakaryocyte cells and in immature telencephalic neurons upon nerve growth factor biogenesis [58]. Analyzing transgenic mice expressing a mutant MAFG (NGF) treatment. It was found that MAFK regulates nerve growth factor protein, lacking the C terminus that were crossed into a Mafg−/− back- (NGF)-promoted neurite generation and neuronal differentiation in ground, it was demonstrated that the C-terminus of MAFG plays a vital PC12 cells and immature telencephalon neurons, implying that it role in platelet gene expression and activation. Intriguingly, the platelet plays a crucial role in neurite outgrowth and its maintenance [51]. count was radically reduced in these compound mutant mice, MAFK was also found to be crucial for neurite outgrowth [52].Com- phenocopying Nfe2−/− mice [59]. This data is of interest, as the C- pound Mafg−/−Mafk−/−mice develop age- and Maff gene dosage- termini of small MAFs are one of the few regions that exhibit a lesser de- dependent neurological defects such as progressive motor disorder, gree of homology [19]. Mafg−/− mice, in addition to having impaired neuronal degeneration, glycine deficiency and also exhibit platelet release, were also shown to compensate for the thrombocyto- alterations in MARE-dependent gene expression. These data highlight penia by increased levels of their proliferative progenitors. Bone mar- the significance of small MAFs in the maintenance of normal CNS func- row transplant studies using wild-type and Mafg−/− mice showed tion [53]. Concentration of small MAFs might play an important role in that absence of MAFG leads to accelerated hematopoietic recovery neurological disorders and these proteins might emerge as novel tar- [60]. Along the same lines, MAFG transcript levels are suppressed in a gets for neuronal diseases. Supporting this notion further, the kinase dose-dependent manner, by human interferon (IFN)-α treatment, AKT, which negatively regulates neuronal differentiation and acts as a which is known to induce thrombocytopenia in chronic hepatitis C neuronal protector against apoptosis, has been shown to suppress patients [61]. MAFK expression in PC12 cells. Besides MAFK, MAFF was also identified as an NGF-responsive immediate-early gene (IEG) in a microarray anal- ysis conducted in PC12 cells [54], suggesting a role for MAFF in neuronal 9. Contribution of small MAFs to cancer pathology cell division and development. It is noteworthy that mechanistically, MAFF has been shown to abate epidermal growth factor (EGF)-induced By virtue through their interaction with CNC transcription factors, MAPK signaling [55], which plays a crucial role in neuronal differentia- small MAF proteins have been clearly linked to carcinogenesis [62,63]. tion. Recently, it has been shown that MAFF is differentially regulated in A few recent studies further exemplify the close association between Parkinson's disease patient-derived olfactory neurosphere-derived cells small MAFs and human cancer pathology. MAFG gene expression has [56]. Transcriptome analysis revealed an induction of MAFF in Par- been found to be significantly lower in smokers who developed lung kinson's disease patients by L-sulforaphane, an inducer of NAD(P)H: cancer when compared to smokers who did not. Interestingly, the quinonereductase (QR1) and a potential candidate for development of study identified several novel single-nucleotide polymorphisms treatment of Parkinson's disease. L-Sulforaphane liberates NFE2L2 (SNPs) including one in the MAFG locus that correlated with MAFG from its cytoplasmic inhibitor, KEAP1, in patients with Parkinson's gene expression and another that was associated with lung cancer sta- disease, whereas in healthy patients there was no such upregulation. tus among smokers [64]. These data revealed a potential role for MAFG MAFG however, was induced in Parkinson's disease patients and in regulating smoking-induced gene expression and it could be specu- healthy individuals by L-sulforaphane. Together, the above studies lated that the MAFG gene locus is involved in lung cancer pathogenesis. strongly suggest a role for small MAFs in neuronal differentiation and Consistently, in a whole genome-profiling study analyzing microRNA function. mir-218 and mRNA levels of bronchial epithelial cells from smokers and non-smokers, MAFG was shown to be one of the candidate genes 8. Small MAFs and thrombocytopenia being upregulated in smokers. 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