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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 -
The Journal of Biological Chemistry Feb 2020The Maf proteins, including c-Maf, MafA, and MafB, are critical transcription factors in myelomagenesis. Previous studies demonstrated that Maf proteins are processed by...
The Maf proteins, including c-Maf, MafA, and MafB, are critical transcription factors in myelomagenesis. Previous studies demonstrated that Maf proteins are processed by the ubiquitin-proteasome pathway, but the mechanisms remain elusive. This study applied MS to identify MafB ubiquitination-associated proteins and found that the ubiquitin-specific protease USP7 was present in the MafB interactome. Moreover, USP7 also interacted with c-Maf and MafA and blocked their polyubiquitination and degradation. Consistently, knockdown of USP7 resulted in Maf protein degradation along with increased polyubiquitination levels. The action of USP7 thus promoted Maf transcriptional activity as evidenced by luciferase assays and by the up-regulation of the expression of Maf-modulated genes. Furthermore, USP7 was up-regulated in myeloma cells, and it was negatively associated with the survival of myeloma patients. USP7 promoted myeloma cell survival, and when it was inhibited by its specific inhibitor P5091, myeloma cell lines underwent apoptosis. These results therefore demonstrated that USP7 is a deubiquitinase of Maf proteins and promotes MM cell survival in association with Maf stability. Given the significance of USP7 and Maf proteins in myeloma genesis, targeting the USP7/Maf axle is a potential strategy to the precision therapy of MM.
Topics: Apoptosis; Carcinogenesis; Cell Proliferation; Cell Survival; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Maf Transcription Factors, Large; MafB Transcription Factor; Male; Multiple Myeloma; Polyubiquitin; Progression-Free Survival; Proteolysis; Proto-Oncogene Proteins c-maf; Thiophenes; Ubiquitin-Specific Peptidase 7; Ubiquitination
PubMed: 31822558
DOI: 10.1074/jbc.RA119.010724 -
Nature Communications Jun 2022While apneas are associated with multiple pathological and fatal conditions, the underlying molecular mechanisms remain elusive. We report that a mutated form of the...
While apneas are associated with multiple pathological and fatal conditions, the underlying molecular mechanisms remain elusive. We report that a mutated form of the transcription factor Mafa (Mafa) that prevents phosphorylation of the Mafa protein leads to an abnormally high incidence of breath holding apneas and death in newborn Mafa mutant mice. This apneic breathing is phenocopied by restricting the mutation to central GABAergic inhibitory neurons and by activation of inhibitory Mafa neurons while reversed by inhibiting GABAergic transmission centrally. We find that Mafa activates the Gad2 promoter in vitro and that this activation is enhanced by the mutation that likely results in increased inhibitory drives onto target neurons. We also find that Mafa inhibitory neurons are absent from respiratory, sensory (primary and secondary) and pontine structures but are present in the vicinity of the hypoglossal motor nucleus including premotor neurons that innervate the geniohyoid muscle, to control upper airway patency. Altogether, our data reveal a role for Mafa phosphorylation in regulation of GABAergic drives and suggest a mechanism whereby reduced premotor drives to upper airway muscles may cause apneic breathing at birth.
Topics: Animals; Apnea; Maf Transcription Factors, Large; Mice; Motor Neurons; Phosphorylation; Promoter Regions, Genetic
PubMed: 35672398
DOI: 10.1038/s41467-022-30825-3 -
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 -
Stem Cell Research & Therapy Nov 2017Transcription factors regulate gene expression through binding to specific enhancer sequences. Pancreas/duodenum homeobox protein 1 (PDX1), Neurogenin-3 (NEUROG3), and... (Review)
Review
Transcription factors regulate gene expression through binding to specific enhancer sequences. Pancreas/duodenum homeobox protein 1 (PDX1), Neurogenin-3 (NEUROG3), and V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA) are transcription factors critical for beta cell development and maturation. NEUROG3 is expressed in endocrine progenitor cells and controls islet differentiation and regeneration. PDX1 is essential for the development of pancreatic exocrine and endocrine cells including beta cells. PDX1 also binds to the regulatory elements and increases insulin gene transcription. Likewise, MAFA binds to the enhancer/promoter region of the insulin gene and drives insulin expression in response to glucose. In addition to those natural roles in beta cell development and maturation, ectopic expression of PDX1, NEUROG3, and/or MAFA has been successfully used to reprogram various cell types into insulin-producing cells in vitro and in vivo, such as pancreatic exocrine cells, hepatocytes, and pluripotent stem cells. Here, we review biological properties of PDX1, NEUROG3, and MAFA, and their applications and limitations for beta cell regenerative approaches. The primary source literature for this review was acquired using a PubMed search for articles published between 1990 and 2017. Search terms include diabetes, insulin, trans-differentiation, stem cells, and regenerative medicine.
Topics: Acinar Cells; Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Cell Transdifferentiation; Cell- and Tissue-Based Therapy; Cellular Reprogramming; Diabetes Mellitus; Gene Expression Regulation; Hepatocytes; Homeodomain Proteins; Humans; Insulin; Insulin-Secreting Cells; Maf Transcription Factors, Large; Mice; Nerve Tissue Proteins; Pluripotent Stem Cells; Signal Transduction; Trans-Activators
PubMed: 29096722
DOI: 10.1186/s13287-017-0694-z -
Trends in Endocrinology and Metabolism:... Sep 2011Analyses in mouse models have revealed crucial roles for MafA (musculoaponeurotic fibrosarcoma oncogene family A) and MafB in islet β cells, with MafB being required... (Review)
Review
Analyses in mouse models have revealed crucial roles for MafA (musculoaponeurotic fibrosarcoma oncogene family A) and MafB in islet β cells, with MafB being required during development and MafA in adults. These two closely related transcription factors regulate many genes essential for glucose sensing and insulin secretion in a cooperative and sequential manner. Significantly, the switch from MafB to MafA expression also appears to be vital for functional maturation of β cells produced by human embryonic stem (hES) cell differentiation. This review summarizes the discovery, distribution, and function of MafA and MafB in rodent pancreatic β cells, and describes some key questions regarding their importance to β cells.
Topics: Animals; Embryonic Stem Cells; Glucose; Insulin; Insulin-Secreting Cells; Maf Transcription Factors, Large; MafB Transcription Factor; Mice; Models, Animal
PubMed: 21719305
DOI: 10.1016/j.tem.2011.05.003 -
Developmental Neurobiology Jan 2022The fate of neurons in the developing brain is largely determined by the combination of transcription factors they express. In particular, stem cells must follow...
The fate of neurons in the developing brain is largely determined by the combination of transcription factors they express. In particular, stem cells must follow different transcriptional cascades during differentiation in order to generate neurons with different neurotransmitter properties, such as glutamatergic and GABAergic neurons. In the mouse cerebral cortex, it has been shown that large Maf family proteins, MafA, MafB and c-Maf, regulate the development of specific types of GABAergic interneurons but are not expressed in glutamatergic neurons. In this study, we examined the expression of large Maf family proteins in the developing mouse olfactory bulb (OB) by immunohistochemistry and found that the cell populations expressing MafA and MafB are almost identical, and most of them express Tbr2. As Tbr2 is expressed in glutamatergic neurons in the OB, we further examined the expression of glutamatergic and GABAergic neuronal markers in MafA and MafB positive cells. The results showed that in the OB, MafA and MafB are expressed exclusively in glutamatergic neurons, but not in GABAergic neurons. We also found that few cells express c-Maf in the OB. These results indicate that, unlike the cerebral cortex, MafA and/or MafB may regulate the development of glutamatergic neurons in the developing OB. This study advances our knowledge about the development of glutamatergic neurons in the olfactory bulb, and also might suggest that mechanisms for the generation of projection neurons and interneurons differ between the cortex and the olfactory bulb, even though they both develop from the telencephalon.
Topics: Animals; Cell Differentiation; Interneurons; Mice; Neurons; Olfactory Bulb; Proto-Oncogene Proteins c-maf; Transcription Factors
PubMed: 34679244
DOI: 10.1002/dneu.22859 -
The EMBO Journal Jun 2022Group-2 innate lymphoid cells (ILC2s), which are involved in type 2 inflammatory diseases such as allergy, can exhibit immunological memory, but the basis of this ILC2...
Group-2 innate lymphoid cells (ILC2s), which are involved in type 2 inflammatory diseases such as allergy, can exhibit immunological memory, but the basis of this ILC2 "trained immunity" has remained unclear. Here, we found that stimulation with IL-33/IL-25 or exposure to the allergen papain induces the expression of the transcription factor c-Maf in mouse ILC2s. Chronic papain exposure results in high production of IL-5 and IL-13 cytokines and lung eosinophil recruitment, effects that are blocked by c-Maf deletion in ILCs. Transcriptomic analysis revealed that knockdown of c-Maf in ILC2s suppresses expression of type 2 cytokine genes, as well as of genes linked to a memory-like phenotype. Consistently, c-Maf was found highly expressed in human adult ILC2s but absent in cord blood and required for cytokine production in isolated human ILC2s. Furthermore, c-Maf-deficient mouse or human ILC2s failed to exhibit strengthened ("trained") responses upon repeated challenge. Thus, the expression of c-Maf is indispensable for optimal type 2 cytokine production and proper memory-like responses in group-2 innate lymphoid cells.
Topics: Animals; Cytokines; Humans; Immunity, Innate; Interleukin-33; Lung; Lymphocytes; Mice; Papain; Proto-Oncogene Proteins c-maf
PubMed: 35467036
DOI: 10.15252/embj.2021109300 -
Blood Dec 2016Multiple myeloma (MM) patients with the t(14;16) translocation have a poor prognosis, and unlike other molecular subgroups, their outcome has not improved with the...
Multiple myeloma (MM) patients with the t(14;16) translocation have a poor prognosis, and unlike other molecular subgroups, their outcome has not improved with the introduction of bortezomib (Bzb). The mechanism underlying innate resistance of MM to Bzb is unknown. In the present study, we have investigated how MAF overexpression impacts resistance to proteasome inhibitor (PI) therapy (Bzb and carfilzomib). High levels of MAF protein were found in t(14;16) cell lines; cell lines from the t(4;14) subgroup had intermediate levels, whereas cell lines from the other subgroups had low levels. High expression of MAF protein in t(14;16) was associated with significantly higher PI half-maximum inhibitory concentration values compared with other molecular subgroups. PI exposure abrogated glycogen synthase kinase 3β (GSK3β)-mediated degradation of MAF protein, resulting in increased MAF protein stability and PI resistance. Subsequent studies using loss-of-function and gain-of-function models showed that silencing MAF led to increased sensitivity to PIs, enhanced apoptosis, and activation of caspase-3, -7, -8, -9, poly (ADP-ribose) polymerase, and lamin A/C. In contrast, overexpression of MAF resulted in increased resistance to PIs and reduced apoptosis. These results define the role of MAF and GSK3 in the resistance of t(14;16) MM to PIs and identifies a novel mechanism by which MAF protein levels are regulated by PIs, which in turn confers resistance to PIs.
Topics: Apoptosis; Caspases; Cell Line, Tumor; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 16; Drug Resistance, Neoplasm; Enzyme Activation; Gene Expression Regulation, Neoplastic; Gene Silencing; Glycogen Synthase Kinase 3 beta; Humans; Immunity, Innate; Lamins; Multiple Myeloma; Phosphorylation; Poly(ADP-ribose) Polymerases; Prognosis; Proteasome Inhibitors; Proteolysis; Proto-Oncogene Proteins c-maf; RNA, Messenger; Translocation, Genetic
PubMed: 27793878
DOI: 10.1182/blood-2016-03-706077 -
The Journal of Biological Chemistry Feb 2016Fibroblast growth factor (FGF) signaling regulates a multitude of cellular processes, including cell proliferation, survival, migration, and differentiation. In the...
Fibroblast growth factor (FGF) signaling regulates a multitude of cellular processes, including cell proliferation, survival, migration, and differentiation. In the vertebrate lens, FGF signaling regulates fiber cell differentiation characterized by high expression of crystallin proteins. However, a direct link between FGF signaling and crystallin gene transcriptional machinery remains to be established. Previously, we have shown that the bZIP proto-oncogene c-Maf regulates expression of αA-crystallin (Cryaa) through binding to its promoter and distal enhancer, DCR1, both activated by FGF2 in cell culture. Herein, we identified and characterized a novel FGF2-responsive region in the c-Maf promoter (-272/-70, FRE). Both c-Maf and Cryaa regulatory regions contain arrays of AP-1 and Ets-binding sites. Chromatin immunoprecipitation (ChIP) assays established binding of c-Jun (an AP-1 factor) and Etv5/ERM (an Ets factor) to these regions in lens chromatin. Analysis of temporal and spatial expression of c-Jun, phospho-c-Jun, and Etv5/ERM in wild type and ERK1/2 deficient lenses supports their roles as nuclear effectors of FGF signaling in mouse embryonic lens. Collectively, these studies show that FGF signaling up-regulates expression of αA-crystallin both directly and indirectly via up-regulation of c-Maf. These molecular mechanisms are applicable for other crystallins and genes highly expressed in terminally differentiated lens fibers.
Topics: Animals; Chick Embryo; Crystallins; Embryo, Mammalian; Fibroblast Growth Factor 2; Humans; Lens, Crystalline; MAP Kinase Signaling System; MCF-7 Cells; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Proto-Oncogene Mas; Proto-Oncogene Proteins c-jun; Proto-Oncogene Proteins c-maf; Response Elements; Up-Regulation
PubMed: 26719333
DOI: 10.1074/jbc.M115.705103