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Blood Aug 2011c-Maf is one of the large Maf (musculoaponeurotic fibrosarcoma) transcription factors that belong to the activated protein-1 super family of basic leucine zipper...
c-Maf is one of the large Maf (musculoaponeurotic fibrosarcoma) transcription factors that belong to the activated protein-1 super family of basic leucine zipper proteins. Despite its overexpression in hematologic malignancies, the physiologic roles c-Maf plays in normal hematopoiesis have been largely unexplored. On a C57BL/6J background, c-Maf(-/-) embryos succumbed from severe erythropenia between embryonic day (E) 15 and E18. Flow cytometric analysis of fetal liver cells showed that the mature erythroid compartments were significantly reduced in c-Maf(-/-) embryos compared with c-Maf(+/+) littermates. Interestingly, the CFU assay indicated there was no significant difference between c-Maf(+/+) and c-Maf(-/-) fetal liver cells in erythroid colony counts. This result indicated that impaired definitive erythropoiesis in c-Maf(-/-) embryos is because of a non-cell-autonomous effect, suggesting a defective erythropoietic microenvironment in the fetal liver. As expected, the number of erythroblasts surrounding the macrophages in erythroblastic islands was significantly reduced in c-Maf(-/-) embryos. Moreover, decreased expression of VCAM-1 was observed in c-Maf(-/-) fetal liver macrophages. In conclusion, these results strongly suggest that c-Maf is crucial for definitive erythropoiesis in fetal liver, playing an important role in macrophages that constitute erythroblastic islands.
Topics: Animals; Cell Communication; Cell Movement; Cell Proliferation; Embryo, Mammalian; Erythroblasts; Erythropoiesis; Fetus; Gene Expression Profiling; Liver; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Microarray Analysis; Proto-Oncogene Proteins c-maf
PubMed: 21628412
DOI: 10.1182/blood-2010-08-300400 -
Virulence Dec 2020MafB proteins are toxins secreted by spp. which are involved in interbacterial competition. Their secretion mechanism has so far not been elucidated. Each strain can...
MafB proteins are toxins secreted by spp. which are involved in interbacterial competition. Their secretion mechanism has so far not been elucidated. Each strain can produce several MafB variants. On the chromosome, the genes are localized on genomic islands also containing genes. MafA proteins have a role in virulence with reported activities in adhesion and transcytosis of pathogenic unrelated to MafB activities. In this study, we investigated the possible involvement of MafA in the transport of MafB across the outer membrane of . In wild-type strains, proteolytic fragments of MafB proteins were detected in the extracellular medium. In the absence of MafA, secretion was abrogated, and, in the case of MafB, full-length and truncated polypeptides were detected inside the cells and inside outer-membrane vesicles. MafB secretion required its cognate MafA, whereas MafB could use any MafA. Heterologous expression in showed that MafB is transported to a cell-surface-exposed, i.e. protease-accessible, location in a MafA-dependent way. MafA itself was found to be localized to the outer membrane, forming large oligomeric complexes. As homologs were found in diverse bacteria, the Maf system represents a new protein secretion system in Gram-negative bacteria.
Topics: Bacterial Outer Membrane; Biological Transport; Escherichia coli; Maf Transcription Factors, Large; MafB Transcription Factor; Neisseria meningitidis; Secretory Pathway
PubMed: 33315509
DOI: 10.1080/21505594.2020.1851940 -
Molecular Vision Jan 2007Maf proteins have been shown to play pivotal roles in lens development in vertebrates. The developing chick lens expresses at least three large Maf proteins. However,...
PURPOSE
Maf proteins have been shown to play pivotal roles in lens development in vertebrates. The developing chick lens expresses at least three large Maf proteins. However, the transcriptional relationship among the three large maf genes and their various roles in transactivating the downstream genes largely remain to be elucidated.
METHODS
Chick embryos were electroporated with wild-type L-maf, c-maf, and mafB by in ovo electroporation, and their effects on gene expression were determined by in situ hybridization using specific probes or by immunostaining. Endogenous gene expression was determined using nonelectroporated samples.
RESULTS
A regulation mechanism exists among the members of maf family gene. An early-expressed member of this gene family typically stimulates the expression of later-expressed members. We also examined the regulation of various lens-expressing genes with a focus on the interaction between different Maf proteins. We found that the transcriptional ability of Maf proteins varies, even when the target is the same, in parallel with their discrete functions. L-Maf and c-Maf have no effect on E-cadherin expression, whereas MafB enhances its expression and thereby impedes lens vesicle formation. This study also revealed that Maf proteins can regulate the expression of gap junction genes, connexins, and their interacting partner, major intrinsic protein (MIP), during lens development. Misexpression of L-Maf and c-Maf induces ectopic expression of Cx43 and MIP; in contrast, MafB appears to have no effect on Cx43, but induces MIP significantly as evidenced from our gain-of-function experiments.
CONCLUSIONS
Our results indicate that large Maf function is indispensable for chick lens initiation and development. In addition, L-Maf positively regulates most of the essential genes in this program and directs a series of molecular events leading to proper formation of the lens.
Topics: Animals; Aquaporins; Cadherins; Chick Embryo; Connexins; Embryo, Mammalian; Embryo, Nonmammalian; Embryonic Development; Eye Proteins; Homeodomain Proteins; Lens, Crystalline; Maf Transcription Factors; Membrane Glycoproteins; Multigene Family; Nerve Tissue Proteins; Transcription, Genetic; Up-Regulation; delta-Crystallins; Homeobox Protein SIX3
PubMed: 17262012
DOI: No ID Found -
Molecular Cell Nov 2007The Maf oncoproteins are b-Zip transcription factors of the AP-1 superfamily. They are involved in developmental, metabolic, and tumorigenic processes. Maf proteins are...
The Maf oncoproteins are b-Zip transcription factors of the AP-1 superfamily. They are involved in developmental, metabolic, and tumorigenic processes. Maf proteins are overexpressed in about 50% of human multiple myelomas. Here, we show that Maf-transforming activity is controlled by GSK-3-dependent phosphorylation and that phosphorylation by GSK-3 can increase the oncogenic activity of a protein. Using microarray analysis, we identify a gene-expression subprogram regulated by GSK-3-mediated Maf phosphorylation involved in extracellular matrix remodeling and relevant to cancer progression. We also demonstrate that GSK-3 triggers MafA sequential phosphorylation on residues S61, T57, T53, and S49, inducing its ubiquitination and degradation. Paradoxically, this phosphorylation increases MafA-transcriptional activity through the recruitment of the coactivator P/CAF. We further demonstrate that P/CAF protects MafA from ubiquitination and degradation, suggesting that, upon the release of the coactivator complex, MafA becomes polyubiquitinated and degraded to allow the response to terminate.
Topics: Amino Acid Sequence; Animals; COS Cells; Cell Line; Cell Transformation, Neoplastic; Chickens; Chlorocebus aethiops; Glycogen Synthase Kinase 3; Humans; Maf Transcription Factors, Large; Molecular Sequence Data; Phosphorylation; Phosphoserine; Phosphothreonine; Protein Processing, Post-Translational; Rats; Transcription, Genetic; Ubiquitination; p300-CBP Transcription Factors
PubMed: 18042454
DOI: 10.1016/j.molcel.2007.11.009 -
The Journal of Experimental Medicine Jan 2020CCR6- group 3 innate lymphoid cells (ILC3s) are mediators of intestinal immunity and barrier function that possess the capacity to acquire type 1 effector features and...
CCR6- group 3 innate lymphoid cells (ILC3s) are mediators of intestinal immunity and barrier function that possess the capacity to acquire type 1 effector features and fully convert into ILC1s. The molecular mechanisms governing such plasticity are undefined. Here, we identified c-Maf as an essential regulator of ILC3 homeostasis and plasticity that limits physiological ILC1 conversion. Phenotypic analysis of effector status in Maf-deficient CCR6- ILC3s, coupled with evaluation of global changes in transcriptome, chromatin accessibility, and transcription factor motif enrichment, revealed that c-Maf enforces ILC3 identity. c-Maf promoted ILC3 accessibility and supported RORγt activity and expression of type 3 effector genes. Conversely, c-Maf antagonized type 1 programming, largely through restraint of T-bet expression and function. Mapping of the dynamic changes in chromatin landscape accompanying CCR6- ILC3 development and ILC1 conversion solidified c-Maf as a gatekeeper of type 1 regulatory transformation and a controller of ILC3 fate.
Topics: Animals; Cell Lineage; Chromatin; Gene Expression Regulation; Homeostasis; Immunity, Innate; Lymphocytes; Mice; Mice, Inbred C57BL; Nuclear Receptor Subfamily 1, Group F, Member 3; Proto-Oncogene Proteins c-maf; Transcription Factors; Transcriptome
PubMed: 31570496
DOI: 10.1084/jem.20191030 -
The International Journal of... 2004Congenital cataracts are rare and occur in developed countries with a frequency of 30 cases among 100,000 births with a further 10 cases being diagnosed during... (Review)
Review
Congenital cataracts are rare and occur in developed countries with a frequency of 30 cases among 100,000 births with a further 10 cases being diagnosed during childhood. They reflect mainly genetically caused developmental alterations in the lens and surrounding ocular tissues. Even if modern Human Genetics has made large steps forward in the characterization of human hereditary disorders, the underlying developmental processes can only be investigated in model organisms. The mouse is such a good model because of its similarity (as a mammal) and its genetic characterization. This review brings together our genetic and developmental knowledge of congenital, human cataracts with the corresponding mouse models. First, early events will be influenced by genes coding for transcription factors like Pax6, Pitx3, Maf or Sox. If the lens is maturing, mutations affecting the lens membranes (aquaporins/Mip, Lim-2 or connexins) or the structural proteins of the cytosol of the lens fiber cells (the crystallins) become more important. From a genetic point of view it becomes obvious that cataract-causing mutations are not distributed randomly. The discovery of a broad variety of genes important for eye and lens development made much progress in the recent years. Nevertheless, there still remains a long list of mutations to be characterized and functionally investigated both in mouse and man indicating a broad genetic heterogeneity in that which clinicians simply refer to as a "cataract".
Topics: Alleles; Animals; Cataract; Cytoskeleton; Cytosol; DNA-Binding Proteins; Disease Models, Animal; Eye Proteins; Gene Expression Regulation, Developmental; High Mobility Group Proteins; Homeodomain Proteins; Humans; Lens, Crystalline; Mice; Mutation; PAX6 Transcription Factor; Paired Box Transcription Factors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-maf; Repressor Proteins; SOXB1 Transcription Factors; Time Factors; Transcription Factors; alpha-Crystallins; beta-Crystallins
PubMed: 15558493
DOI: 10.1387/ijdb.041854jg -
Chemistry & Biology Nov 2013Maf (for multicopy associated filamentation) proteins represent a large family of conserved proteins implicated in cell division arrest but whose biochemical activity...
Maf (for multicopy associated filamentation) proteins represent a large family of conserved proteins implicated in cell division arrest but whose biochemical activity remains unknown. Here, we show that the prokaryotic and eukaryotic Maf proteins exhibit nucleotide pyrophosphatase activity against 5-methyl-UTP, pseudo-UTP, 5-methyl-CTP, and 7-methyl-GTP, which represent the most abundant modified bases in all organisms, as well as against canonical nucleotides dTTP, UTP, and CTP. Overexpression of the Maf protein YhdE in E. coli cells increased intracellular levels of dTMP and UMP, confirming that dTTP and UTP are the in vivo substrates of this protein. Crystal structures and site-directed mutagenesis of Maf proteins revealed the determinants of their activity and substrate specificity. Thus, pyrophosphatase activity of Maf proteins toward canonical and modified nucleotides might provide the molecular mechanism for a dual role of these proteins in cell division arrest and house cleaning.
Topics: Bacillus subtilis; Conserved Sequence; Crystallography, X-Ray; Escherichia coli; Escherichia coli Proteins; Humans; Maf Transcription Factors; Models, Molecular; Mutagenesis, Site-Directed; Nucleotides; Pyrophosphatases; Saccharomyces cerevisiae; Salmonella typhimurium; Substrate Specificity
PubMed: 24210219
DOI: 10.1016/j.chembiol.2013.09.011 -
Experimental Animals Aug 2021The large MAF transcription factor group is a group of transcription factors with an acidic region, a basic region, and a leucine zipper region. Four types of MAF, MAFA,...
The large MAF transcription factor group is a group of transcription factors with an acidic region, a basic region, and a leucine zipper region. Four types of MAF, MAFA, MAFB, c-MAF, and NRL, have been identified in humans and mice. In order to elucidate the functions of the large MAF transcription factor group in vivo, our research group created genetically modified MAFA-, MAFB-, and c-MAF-deficient mice and analyzed their phenotypes. MAFA is expressed in pancreatic β cells and is essential for insulin transcription and secretion. MAFB is essential for the development of pancreatic endocrine cells, formation of inner ears, podocyte function in the kidneys, and functional differentiation of macrophages. c-MAF is essential for lens formation and osteoblast differentiation. Furthermore, a single-base mutation in genes encoding the large MAF transcription factor group causes congenital renal disease, eye disease, bone disease, diabetes, and tumors in humans. This review describes the functions of large MAF transcription factors in vivo and their relationships with human diseases.
Topics: Animals; Bone Diseases; Diabetes Mellitus; Eye Diseases; Humans; Kidney Diseases; Maf Transcription Factors, Large; Mice; Mutation; Neoplasms
PubMed: 33762508
DOI: 10.1538/expanim.21-0027 -
Human Molecular Genetics May 2007MAF, one of a family of large Maf bZIP transcription factors, is mutated in human developmental ocular disorders that include congenital cataract, microcornea, coloboma...
MAF, one of a family of large Maf bZIP transcription factors, is mutated in human developmental ocular disorders that include congenital cataract, microcornea, coloboma and anterior segment dysgenesis. Expressed early in the developing lens vesicle, it is central to regulation of lens crystallin gene expression. We report a semi-dominant mouse c-Maf mutation recovered after ENU mutatgenesis which results in the substitution, D90V, at a highly conserved residue within the N-terminal 35 amino-acid minimal transactivation domain (MTD). Unlike null and loss-of-function c-Maf mutations, which cause severe runting and renal abnormalities, the phenotype caused by the D90V mutation is isolated cataract. In reporter assays, D90V results in increased promoter activation, a situation similar to MTD mutations of NRL that also cause human disease. In contrast to wild-type protein, the c-Maf D90V mutant protein is not inhibited by protein kinase A-dependent pathways. The MTD of large Maf proteins has been shown to interact with the transcriptional co-activator p300 and we demonstrate that c-Maf D90V enhances p300 recruitment in a cell-type dependent manner. We observed the same for the pathogenic human NRL MTD mutation S50T, which suggests a common mechanism of action.
Topics: Amino Acid Substitution; Animals; Binding Sites; COS Cells; Cataract; Cell Line, Tumor; Chlorocebus aethiops; E1A-Associated p300 Protein; Humans; Lens, Crystalline; Mice; Mice, Mutant Strains; Mutation; Protein Binding; Proto-Oncogene Proteins c-maf; Signal Transduction; Two-Hybrid System Techniques
PubMed: 17374726
DOI: 10.1093/hmg/ddm048 -
Acta Pharmacologica Sinica Dec 2019c-Maf is a critical oncogenic transcription factor that contributes to myelomagenesis. Our previous studies demonstrated that the deubiquitinase USP5 stabilizes c-Maf...
c-Maf is a critical oncogenic transcription factor that contributes to myelomagenesis. Our previous studies demonstrated that the deubiquitinase USP5 stabilizes c-Maf and promotes myeloma cell proliferation and survival; therefore, the USP5/c-Maf axis could be a potential target for myeloma therapy. As a concept of principle, the present study established a USP5/c-Maf-based luciferase system that was used to screen an FDA-approved drug library. It was found that mebendazole, a typical anthelmintic drug, preferentially induced apoptosis in c-Maf-expressing myeloma cells. Moreover, oral administration of mebendazole delayed the growth of human myeloma xenografts in nude mice but did not show overt toxicity. Further studies showed that the selective antimyeloma activity of mebendazole was associated with the inhibition of the USP5/c-Maf axis. Mebendazole downregulated USP5 expression and disrupted the interaction between USP5 and c-Maf, thus leading to increased levels of c-Maf ubiquitination and subsequent c-Maf degradation. Mebendazole inhibited c-Maf transcriptional activity, as confirmed by both luciferase assays and expression measurements of c-Maf downstream genes. In summary, this study identified mebendazole as a USP5/c-Maf inhibitor that could be developed as a novel antimyeloma agent.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cyanoacrylates; Drug Repositioning; Drug Synergism; Female; HEK293 Cells; Humans; Mebendazole; Mice, Inbred BALB C; Mice, Nude; Multiple Myeloma; Proof of Concept Study; Protein Binding; Proto-Oncogene Proteins c-maf; Pyridines; Ubiquitin-Specific Proteases; Ubiquitination; Xenograft Model Antitumor Assays
PubMed: 31197245
DOI: 10.1038/s41401-019-0249-1