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Development (Cambridge, England) Dec 2022There are fundamental differences in how neonatal and adult intestines absorb nutrients. In adults, macromolecules are broken down into simpler molecular components in...
There are fundamental differences in how neonatal and adult intestines absorb nutrients. In adults, macromolecules are broken down into simpler molecular components in the lumen of the small intestine, then absorbed. In contrast, neonates are thought to rely on internalization of whole macromolecules and subsequent degradation in the lysosome. Here, we identify the Maf family transcription factors MAFB and c-MAF as markers of terminally differentiated intestinal enterocytes throughout life. The expression of these factors is regulated by HNF4α and HNF4γ, master regulators of enterocyte cell fate. Loss of Maf factors results in a neonatal-specific failure to thrive and loss of macromolecular nutrient uptake. RNA-Seq and CUT&RUN analyses defined an endo-lysosomal program as being downstream of these transcription factors. We demonstrate major transcriptional changes in metabolic pathways, including fatty acid oxidation and increases in peroxisome number, in response to loss of Maf proteins. Finally, we show that loss of BLIMP1, a repressor of adult enterocyte genes, shows highly overlapping changes in gene expression and similar defects in macromolecular uptake. This work defines transcriptional regulators that are necessary for nutrient uptake in neonatal enterocytes.
Topics: Mice; Animals; Maf Transcription Factors; Biological Transport; Nutrients; Cell Differentiation; Transcription Factors; Proto-Oncogene Proteins c-maf
PubMed: 36504079
DOI: 10.1242/dev.201251 -
Journal of Biochemistry Jun 2007Maf family transcription factors are regulators of tissue-specific gene expression and cell-differentiation in a wide variety of tissues and are also involved in human... (Review)
Review
Maf family transcription factors are regulators of tissue-specific gene expression and cell-differentiation in a wide variety of tissues and are also involved in human diseases and oncogenic transformation. To establish tissue-specific expression, Maf binds to Maf-recognition elements (MAREs) in the regulatory regions of target genes, and functionally interacts with other transcription factors. For example, L-Maf and c-Maf, which are specifically expressed in developing lens cells, act synergistically with Sox proteins to induce lens-specific crystalline genes. MafA, a beta-cell-specific member of the Maf family, activates the insulin gene promoter synergistically with Pdx1 and Beta2 to establish beta-cell specific expression. Furthermore, in beta-cells, MafA activity is regulated at both the transcriptional and post-translational levels by glucose and oxidative stress. This review summarizes the functions and roles of Maf in various biological processes and recent progress in elucidating the mechanisms whereby Maf proteins regulate transcription.
Topics: Animals; Base Sequence; Crystallins; Gene Expression Regulation; Gene Silencing; Humans; Insulin-Secreting Cells; Lens, Crystalline; Maf Transcription Factors; Models, Biological; Molecular Sequence Data; Promoter Regions, Genetic; Sex-Determining Region Y Protein; Tissue Distribution; Transcription Factors
PubMed: 17569705
DOI: 10.1093/jb/mvm105 -
Cancer Science Feb 2007Many studies on carcinogenesis carried out early in the last century are united on the consensus that cancer is a genetic disease. Cancer cells typically display gene... (Review)
Review
Many studies on carcinogenesis carried out early in the last century are united on the consensus that cancer is a genetic disease. Cancer cells typically display gene dysfunction and endogenous or exogenous insults resulting in gene dysfunction are often carcinogenic. Recent advances in stem cell biology added the new concept that cancer originates from a single cancer-initiating cell. To understand the molecular basis of carcinogenesis from the beginning to the full acquirement of malignancy, factors concerned with carcinogenesis were categorized into three groups: those guarding and stabilizing genomes, those regulating cell proliferation, and those conferring resistance to various micro-environmental stresses. One example of particular interest is the Keap1-Nrf2 system since, according to recent studies, it has turned out to be ambivalent. Nrf2 heterodimerizes with small Maf protein to strongly activate transcription through the Maf recognition element (MARE) and Keap1 is an inhibitory regulator of Nrf2. The genes regulated by Nrf2 are very important for cellular protection of the genome from xenobiotic and oxidative stresses and, consequently, for preventing carcinogenesis. This implies that enhancing Nrf2 activity is a promising method for thwarting cancer. On the contrary, the constitutive activation of Nrf2 due to mutations in the keap1 gene is characteristically observed in lung cancer cells, suggesting that induced expression of Nrf2 target genes favors the prevalence of cancer cells.
Topics: Animals; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Humans; Maf Transcription Factors; Oxidative Stress; Response Elements; Transcription, Genetic
PubMed: 17129360
DOI: 10.1111/j.1349-7006.2006.00358.x -
The Journal of Clinical Investigation Aug 2018SUMOylation is involved in the development of several inflammatory diseases, but the physiological significance of SUMO-modulated c-Maf in autoimmune diabetes is not...
SUMOylation is involved in the development of several inflammatory diseases, but the physiological significance of SUMO-modulated c-Maf in autoimmune diabetes is not completely understood. Here, we report that an age-dependent attenuation of c-Maf SUMOylation in CD4+ T cells is positively correlated with the IL-21-mediated diabetogenesis in NOD mice. Using 2 strains of T cell-specific transgenic NOD mice overexpressing wild-type c-Maf (Tg-WTc) or SUMOylation site-mutated c-Maf (Tg-KRc), we demonstrated that Tg-KRc mice developed diabetes more rapidly than Tg-WTc mice in a CD4+ T cell-autonomous manner. Moreover, SUMO-defective c-Maf preferentially transactivated Il21 to promote the development of CD4+ T cells with an extrafollicular helper T cell phenotype and expand the numbers of granzyme B-producing effector/memory CD8+ T cells. Furthermore, SUMO-defective c-Maf selectively inhibited recruitment of Daxx/HDAC2 to the Il21 promoter and enhanced histone acetylation mediated by CREB-binding protein (CBP) and p300. Using pharmacological interference with CBP/p300, we illustrated that CBP30 treatment ameliorated c-Maf-mediated/IL-21-based diabetogenesis. Taken together, our results show that the SUMOylation status of c-Maf has a stronger regulatory effect on IL-21 than the level of c-Maf expression, through an epigenetic mechanism. These findings provide new insights into how SUMOylation modulates the pathogenesis of autoimmune diabetes in a T cell-restricted manner and on the basis of a single transcription factor.
Topics: Amino Acid Substitution; Animals; Benzimidazoles; Binding Sites; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Epigenesis, Genetic; Interleukins; Isoxazoles; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mice, Transgenic; Models, Biological; Mutant Proteins; Promoter Regions, Genetic; Proto-Oncogene Proteins c-maf; Sumoylation; Transcriptional Activation; p300-CBP Transcription Factors
PubMed: 30059018
DOI: 10.1172/JCI98786 -
Human Mutation Apr 2018Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other... (Review)
Review
Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other components of the eye or in nonocular tissues. We comprehensively describe here all the variants in FOXE3, HSF4, MAF, and PITX3 genes linked to human developmental defects. A total of 52 variants for FOXE3, 18 variants for HSF4, 20 variants for MAF, and 19 variants for PITX3 identified so far in isolated cases or within families are documented. This effort reveals FOXE3, HSF4, MAF, and PITX3 to have 33, 16, 18, and 7 unique causal mutations, respectively. Loss-of-function mutant animals for these genes have served to model the pathobiology of the associated human defects, and we discuss the currently known molecular function of these genes, particularly with emphasis on their role in ocular development. Finally, we make the detailed FOXE3, HSF4, MAF, and PITX3 variant information available in the Leiden Online Variation Database (LOVD) platform at https://www.LOVD.nl/FOXE3, https://www.LOVD.nl/HSF4, https://www.LOVD.nl/MAF, and https://www.LOVD.nl/PITX3. Thus, this article informs on key variants in transcription factor genes linked to cataract, aphakia, corneal opacity, glaucoma, microcornea, microphthalmia, anterior segment mesenchymal dysgenesis, and Ayme-Gripp syndrome, and facilitates their access through Web-based databases.
Topics: Animals; Cataract; Eye Abnormalities; Facies; Forkhead Transcription Factors; Growth Disorders; Hearing Loss, Sensorineural; Heat Shock Transcription Factors; Homeodomain Proteins; Humans; Intellectual Disability; Mutation; Proto-Oncogene Proteins c-maf; Transcription Factors
PubMed: 29314435
DOI: 10.1002/humu.23395 -
The Journal of Biological Chemistry Apr 2011Until recently, effector T helper (Th) cells have been classified into two subsets, Th1 and Th2 cells. Since the discovery of Th17 cells, which produce IL-17, much...
Until recently, effector T helper (Th) cells have been classified into two subsets, Th1 and Th2 cells. Since the discovery of Th17 cells, which produce IL-17, much attention has been given to Th17 cells, mainly because they have been implicated in the pathogenesis of various inflammatory diseases. We have performed transcriptome analysis combined with factor analysis and revealed that the expression level of c-Maf, which is considered to be important for Th2 differentiation, increases significantly during the course of Th17 differentiation. The IL-23 receptor (IL-23R), which is important for Th17 cells, is among putative transcriptional targets of c-Maf. Interestingly, the analysis of c-Maf transgenic Th cells revealed that the overexpression of c-Maf did not lead to the acceleration of the early stage of Th17 differentiation but rather to the expansion of memory phenotype cells, particularly with Th1 and Th17 traits. Consistently, mouse wild-type memory Th cells expressed higher mRNA levels of c-Maf, IL-23R, IL-17, and IFN-γ than control cells; in contrast, Maf(-/-) memory Th cells expressed lower mRNA levels of those molecules. Thus, we propose that c-Maf is important for the development of memory Th cells, particularly memory Th17 cells and Th1 cells.
Topics: Animals; Cell Differentiation; Cell Proliferation; Gene Expression Profiling; Immunologic Memory; Mice; Mice, Knockout; Proto-Oncogene Proteins c-maf; RNA, Messenger; Th1 Cells; Th17 Cells; Transcriptional Activation
PubMed: 21402704
DOI: 10.1074/jbc.M111.218867 -
Biochemical and Biophysical Research... Jul 2004Small Maf proteins play critical roles on morphogenesis and homeostasis through associating with CNC proteins. To date, three small Maf proteins, MafF, MafG, and MafK,...
Small Maf proteins play critical roles on morphogenesis and homeostasis through associating with CNC proteins. To date, three small Maf proteins, MafF, MafG, and MafK, have been reported in vertebrates, which share redundant functions. In this study, we tried to identify and characterize small Maf proteins in zebrafish to elucidate their conservation and diversity in the fish kingdom. We identified homolog genes of MafG and MafK but not MafF in zebrafish, indicating the former two are conserved among vertebrates. In addition, a novel type of small Maf protein MafT was identified. MafT protein bound MARE sequence as a homodimer or heterodimers with zebrafish Nrf2 or p45 Nfe2. Co-overexpression of MafT and Nrf2 synergistically activated MARE-mediated gene expression in zebrafish embryos. These results indicated that MafT is a new member of small Maf proteins and involved in the Nrf2-dependent gene regulation in cellular defense system.
Topics: Amino Acid Sequence; Animals; Cells, Cultured; Conserved Sequence; DNA-Binding Proteins; Gene Expression Regulation, Enzymologic; Maf Transcription Factors, Small; Molecular Sequence Data; NF-E2-Related Factor 2; Phylogeny; Sequence Analysis, Protein; Sequence Homology, Amino Acid; Trans-Activators; Transcription Factors; Zebrafish; Zebrafish Proteins
PubMed: 15207702
DOI: 10.1016/j.bbrc.2004.05.131 -
The ubiquitin-conjugating enzyme UBE2O modulates c-Maf stability and induces myeloma cell apoptosis.Journal of Hematology & Oncology Jul 2017UBE2O is proposed as a ubiquitin-conjugating enzyme, but its function was largely unknown.
BACKGROUND
UBE2O is proposed as a ubiquitin-conjugating enzyme, but its function was largely unknown.
METHODS
Mass spectrometry was applied to identify c-Maf ubiquitination-associated proteins. Immunoprecipitation was applied for c-Maf and UBE2O interaction. Immunoblotting was used for Maf protein stability. Luciferase assay was used for c-Maf transcriptional activity. Lentiviral infections were applied for UBE2O function in multiple myeloma (MM) cells. Flow cytometry and nude mice xenografts were applied for MM cell apoptosis and tumor growth assay, respectively.
RESULTS
UBE2O was found to interact with c-Maf, a critical transcription factor in MM, by the affinity purification/tandem mass spectrometry assay and co-immunoprecipitation assays. Subsequent studies showed that UBE2O mediated c-Maf polyubiquitination and degradation. Moreover, UBE2O downregulated the transcriptional activity of c-Maf and the expression of cyclin D2, a typical gene modulated by c-Maf. DNA microarray revealed that UBE2O was expressed in normal bone marrow cells but downregulated in MGUS, smoldering MM and MM cells, which was confirmed by RT-PCR in primary MM cells, suggesting its potential role in myeloma pathophysiology. When UBE2O was restored, c-Maf protein in MM cells was significantly decreased and MM cells underwent apoptosis. Furthermore, the human MM xenograft in nude mice showed that re-expression of UBE2O delayed the growth of myeloma xenografts in nude mice in association with c-Maf downregulation and activation of the apoptotic pathway.
CONCLUSIONS
UBE2O mediates c-Maf polyubiquitination and degradation, induces MM cell apoptosis, and suppresses myeloma tumor growth, which provides a novel insight in understanding myelomagenesis and UBE2O biology.
Topics: Animals; Apoptosis; Cell Line, Tumor; Cells, Cultured; HEK293 Cells; Humans; Mice, Nude; Multiple Myeloma; Protein Interaction Maps; Protein Stability; Proto-Oncogene Proteins c-maf; Ubiquitin-Conjugating Enzymes; Ubiquitination
PubMed: 28673317
DOI: 10.1186/s13045-017-0499-7 -
JCI Insight Mar 2023The transcription factor c-Maf has been widely studied and has been reported to play a critical role in embryonic kidney development; however, the postnatal functions of...
The transcription factor c-Maf has been widely studied and has been reported to play a critical role in embryonic kidney development; however, the postnatal functions of c-Maf in adult kidneys remain unknown as c-Maf-null C57BL/6J mice exhibit embryonic lethality. In this study, we investigated the role of c-Maf in adult mouse kidneys by comparing the phenotypes of tamoxifen-inducible (TAM-inducible) c-Maf-knockout mice (c-Maffl/fl; CAG-Cre-ERTM mice named "c-MafΔTAM") with those of c-Maffl/fl control mice, 10 days after TAM injection [TAM(10d)]. In addition, we examined the effects of c-Maf deletion on diabetic conditions by injecting the mice with streptozotocin, 4 weeks before TAM injection. c-MafΔTAM mice displayed primary glycosuria caused by sodium-glucose cotransporter 2 (Sglt2) and glucose transporter 2 (Glut2) downregulation in the kidneys without diabetes, as well as morphological changes and life-threatening injuries in the kidneys on TAM(10d). Under diabetic conditions, c-Maf deletion promoted recovery from hyperglycemia and suppressed albuminuria and diabetic nephropathy by causing similar effects as did Sglt2 knockout and SGLT2 inhibitors. In addition to demonstrating the potentially unique gene regulation of c-Maf, these findings highlight the renoprotective effects of c-Maf deficiency under diabetic conditions and suggest that c-Maf could be a novel therapeutic target gene for treating diabetic nephropathy.
Topics: Animals; Mice; Diabetes Mellitus; Diabetic Nephropathies; Mice, Inbred C57BL; Proto-Oncogene Proteins c-maf; Sodium-Glucose Transporter 2; Streptozocin; Transcription Factors
PubMed: 36787192
DOI: 10.1172/jci.insight.163306 -
Cell Communication and Signaling : CCS Feb 2021The oncogenic transcript factor c-Maf is stabilized by the deubiquitinase Otub1 and promotes myeloma cell proliferation and confers to chemoresistance. Inhibition of the...
BACKGROUND
The oncogenic transcript factor c-Maf is stabilized by the deubiquitinase Otub1 and promotes myeloma cell proliferation and confers to chemoresistance. Inhibition of the Otub1/c-Maf axis is a promising therapeutic target, but there are no inhibitors reported on this specific axis.
METHODS
A luciferase assay was applied to screen potential inhibitors of Otub1/c-Maf. Annexin V staining/flow cytometry was applied to evaluate cell apoptosis. Immunoprecipitation was applied to examine protein ubiquitination and interaction. Xenograft models in nude mice were used to evaluate anti-myeloma activity of AVT.
RESULTS
Acevaltrate (AVT), isolated from Valeriana glechomifolia, was identified based on a bioactive screen against the Otub1/c-Maf/luciferase system. AVT disrupts the interaction of Otub1/c-Maf thus inhibiting Otub1 activity and leading to c-Maf polyubiquitination and subsequent degradation in proteasomes. Consistently, AVT inhibits c-Maf transcriptional activity and downregulates the expression of its target genes key for myeloma growth and survival. Moreover, AVT displays potent anti-myeloma activity by triggering myeloma cell apoptosis in vitro and impairing myeloma xenograft growth in vivo but presents no marked toxicity.
CONCLUSIONS
The natural product AVT inhibits the Otub1/c-Maf axis and displays potent anti-myeloma activity. Given its great safety and efficacy, AVT could be further developed for MM treatment. Video Abstract.
Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line; Cell Survival; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Female; Humans; Iridoids; Mice, Inbred BALB C; Mice, Nude; Multiple Myeloma; Proto-Oncogene Proteins c-maf; Mice
PubMed: 33627137
DOI: 10.1186/s12964-020-00676-w