Disease relevance of Maf

• Adenovirus mediated introduction of c-maf gene into the mouse fibroblast cell line C3H10T1/2 strongly induced CTGF expression [1].
• Insertion of MelARV in BL6 melanoma cells resulted in the up-regulation of c-maf [2].
• Since mice heterozygous for knockouts of Maf show no cataracts, this suggests that the Ofl R291Q mutant protein has a dominant effect [3].
• Homozygotes for Ofl and for Maf null mutations are similar but a new effect, renal tubular nephritis, was found in Ofl homozygotes surviving beyond 4 weeks, which may contribute to early lethality [3].
• Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response [4].

High impact information on Maf

• When the mafG null mutants were bred to small Maf-overexpressing transgenic animals, both loss- and gain-of-function phenotypes were reversed [5].
• The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4 [6].
• Whereas homodimers of the small Maf proteins act as negative regulators, heterodimers composed of Maf and p45 support active transcription in vivo [7].
• These results provide direct evidence that the small Maf transcription factors are vital participants in embryonic development and cellular differentiation [8].
• CD4+ T cells and NK T cells from c-maf(-/-) mice were markedly deficient in IL-4 production [9].

Biological context of Maf

• We have used gene targeting to replace Maf coding sequences with those of lacZ, and have carried out a comprehensive analysis of embryonic expression and the homozygous mutant phenotype in the eye [10].
• Our results indicate that Maf directly activates many if not all of the (beta)-crystallin genes, and suggest a model for coordinating cell cycle withdrawal with terminal differentiation [10].
• Recombinant Maf protein binds to T-MARE sites in the (alpha)A-, (beta)B2-, and (beta)A4-crystallin promoters but fails to bind to a point mutation in the (alpha)A-crystallin promoter that has been shown previously to be required for promoter function [10].
• Cyclosporin A and FK506, which target calcineurin and thereby inhibit TCR-mediated Ca(2+) signal pathways, block IL-6-mediated c-Maf expression [11].
• Reporter transfection analysis using C3H10T1/2 cells shows that c-Maf stimulates a CTGF reporter gene [1].

Anatomical context of Maf

• Maf is expressed in the lens vesicle after invagination, and becomes highly upregulated in the equatorial zone, the site at which self-renewing anterior epithelial cells withdraw from the cell cycle and terminally differentiate into posterior fiber cells [10].
• Little is known about the mechanism that guides c-Maf regulation during early T cell activation [11].
• As is the case for the c-maf gene, overexpression of the mafB gene induces transformation of chicken embryo fibroblasts in vitro [12].
• We previously found that c-maf and mafB are strongly expressed in hypertrophic chondrocytes during cartilage development [1].
• Our data indicate that c-maf is a common insertion site of MelARV in BL6, Meli-A1 and Meli-BL melanomas, whereas no such insertion site was found in the melanocytes infected with MelARV but not malignantly transformed [13].

Associations of Maf with chemical compounds

• Gel shift assays using lens nuclear extracts demonstrated interactions of Pax6, Maf, and retinoic acid nuclear receptor proteins with two lens-specific regions, the distal LSR1 (-147/-118) and proximal LSR2 (-78/-40), of the alphaB-crystallin promoter [14].
• Bach2 is a member of the BTB-basic region leucine zipper factor family and represses transcription activity directed by the 12-O-tetradecanoylphorbol-13-acetate response element, the Maf recognition element, and the antioxidant-responsive element [15].
• Because MafA, MafB, and c-Maf were each capable of specifically binding to and activating insulin C1 element-mediated expression, our results suggest that all of these factors play a role in islet beta-cell function [16].
• Oxidative stress abolishes leptomycin B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element [17].
• This protein controls the glucose-regulated and pancreatic beta-cell-specific expression of the insulin gene through a cis-regulatory element called RIPE3b/MARE (Maf-recognition element) [18].

Physical interactions of Maf

• Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1 [19].
• Electrophoresis mobility shift assay and DNase I footprinting analysis show that at least three Pax6-binding sites are located in the 5'-flanking and 5'-non-coding regions of the rat c-maf gene [20].
• Bach2 is a B-cell-specific transcription repressor interacting with the small Maf proteins whose expression is high only before the plasma cell stage [21].
• Impaired IL-4 production by CD8+ T cells in NOD mice is related to a defect of c-Maf binding to the IL-4 promoter [22].
• In this study we sought to determine the identity of the specific constituent that collaboratively interacts with Nrf2 to bind to the Maf recognition element in vivo [23].

Regulatory relationships of Maf

• IL-6 induces similar c-Maf expression in protein kinase Ctheta-deficient CD4(+) T cells [11].
• We previously found that c-Maf, c-Jun, and Pax6 bind to and stimulate the c-maf gene [24].
• Up-regulation of c-Maf was dependent on Ca2+/nuclear factor of activated T cell (NFAT) and, together with IL-4 production, could be rescued in Vav1-/- T cells by Ca2+ ionophore [25].
• These results suggest that Bach2 regulates AP-1- and Maf-dependent gene expression during development of neuronal and lens cells and that its activity may be regulated by nuclear export in these cells [26].
• MMP-13 is known to be regulated by AP-1 and may also be a target of c-Maf [27].

Other interactions of Maf

• Through formation of numerous bZip dimers, the Maf family proteins along with the AP-1 components should provide great diversity in transcriptional regulation for a wide variety of genes [12].
• Taken together, these data indicate that the CTGF gene is a target of c-Maf and Lc-Maf in cartilage development [1].
• The transcription factor c-Maf plays a critical and selective role in IL-4 gene transcription [11].
• Several transcription factors such as Pax6, Sox1, and L-Maf have been shown to regulate lens development [28].
• Deficient IL-4 production was restored by retrovirus-mediated Vav1 expression, but only partially by retroviral c-Maf expression [25].

Analytical, diagnostic and therapeutic context of Maf

• Chromatin immunoprecipitations established in vivo interactions of Pax6 and c-Maf with the alphaA-crystallin promoter in lens cells [29].
• Chromatin immunoprecipitation revealed that small Maf proteins participate in both repression and activation of ho-1 [30].
• The heterodimer of Bach2/MafK bound to the Maf recognition element located upstream of the Prdm1 promoter in an electrophoretic mobility shift assay [31].
• BrdU and TUNEL analyses show normal proliferation rate and apoptosis in the c-maf-null [27].
• Immunocytochemistry of 4-week-old mouse kidney using anti-c-maf antisera was also performed [32].

References