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Biochemical and Biophysical Research... Apr 2016The large Maf transcription factors c-Maf and MafB are expressed in macrophage-lineage hematopoietic cells, but the expression patterns of MafB and c-Maf in macrophage...
The large Maf transcription factors c-Maf and MafB are expressed in macrophage-lineage hematopoietic cells, but the expression patterns of MafB and c-Maf in macrophage subtypes and tissue-resident macrophages have not been fully analyzed. First, we analyzed MafB and c-Maf protein expression in tissue-resident macrophages. Mouse lymph nodes, spleens, lungs, and kidneys were subjected to immunohistochemistry using anti-MafB and anti-c-Maf. Both MafB and c-Maf signals were observed in lymph node macrophages. In the splenic macrophages the MafB signal was detected by anti-MafB, but the c-Maf signal was not detected. No expression of c-Maf or MafB was detected in macrophages in the lung and kidney. Flow cytometry analysis revealed a similar pattern of GFP expression in Mafb/GFP knock-in heterozygous mice. To analyze these different expression patterns in greater detail, we examined the expression of MafB and c-Maf by quantitative RT-PCR in different cytokine- or LPS-induced macrophages in vitro. MafB expression was induced by IL-10 or IL-4 with IL-13 and was reduced by LPS or GM-CSF. By contrast, c-Maf expression was induced by IL-10 and reduced by IL-4 with IL-13 or GM-CSF. These results indicate that MafB and c-Maf have different expression patterns in macrophages, suggesting differences in function.
Topics: Animals; Bronchoalveolar Lavage; Cell Separation; Flow Cytometry; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; Green Fluorescent Proteins; Heterozygote; Interleukin-10; Interleukin-13; Interleukin-4; Kidney; Lipopolysaccharides; Lung; Macrophages; MafB Transcription Factor; Mice; Mice, Inbred C57BL; Mice, Transgenic; Proto-Oncogene Proteins c-maf; Real-Time Polymerase Chain Reaction; Signal Transduction; Tissue Distribution
PubMed: 26996125
DOI: 10.1016/j.bbrc.2016.03.063 -
The Journal of Clinical Investigation Apr 2020Macrophages have been linked to tumor initiation, progression, metastasis, and treatment resistance. However, the transcriptional regulation of macrophages driving the...
Macrophages have been linked to tumor initiation, progression, metastasis, and treatment resistance. However, the transcriptional regulation of macrophages driving the protumor function remains elusive. Here, we demonstrate that the transcription factor c-Maf is a critical controller for immunosuppressive macrophage polarization and function in cancer. c-Maf controls many M2-related genes and has direct binding sites within a conserved noncoding sequence of the Csf-1r gene and promotes M2-like macrophage-mediated T cell suppression and tumor progression. c-Maf also serves as a metabolic checkpoint regulating the TCA cycle and UDP-GlcNAc biosynthesis, thus promoting M2-like macrophage polarization and activation. Additionally, c-Maf is highly expressed in tumor-associated macrophages (TAMs) and regulates TAM immunosuppressive function. Deletion of c-Maf specifically in myeloid cells results in reduced tumor burden with enhanced antitumor T cell immunity. Inhibition of c-Maf partly overcomes resistance to anti-PD-1 therapy in a subcutaneous LLC tumor model. Similarly, c-Maf is expressed in human M2 and tumor-infiltrating macrophages/monocytes as well as circulating monocytes of human non-small cell lung carcinoma (NSCLC) patients and critically regulates their immunosuppressive activity. The natural compound β-glucan downregulates c-Maf expression on macrophages, leading to enhanced antitumor immunity in mice. These findings establish a paradigm for immunosuppressive macrophage polarization and transcriptional regulation by c-Maf and suggest that c-Maf is a potential target for effective tumor immunotherapy.
Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Humans; Immunity, Cellular; Lung Neoplasms; Macrophage Activation; Macrophages; Male; Mice; Mice, Knockout; Monocytes; Neoplasms, Experimental; Proto-Oncogene Proteins c-maf; T-Lymphocytes
PubMed: 31945018
DOI: 10.1172/JCI131335 -
Cell Death & Disease Sep 2020As a deubiqutinase Otub1 stabilizes and promotes the oncogenic activity of the transcription factor c-Maf in multiple myeloma (MM), a malignancy of plasma cells. In the...
As a deubiqutinase Otub1 stabilizes and promotes the oncogenic activity of the transcription factor c-Maf in multiple myeloma (MM), a malignancy of plasma cells. In the screen for bioactive inhibitors of the Otub1/c-Maf axis for MM treatment, nanchangmycin (Nam), a polyketide antibiotic, was identified to suppress c-Maf activity in the presence of Otub1. By suppressing Otub1, Nam induces c-Maf polyubiquitination and subsequent degradation in proteasomes but does not alter its mRNA level. Consistently, Nam downregulates the expression of CCND2, ARK5, and ITGB7, the downstream genes regulated by c-Maf, and promotes MM cell apoptosis as evidenced by PARP and Caspase-3 cleavage, as well as Annexin V staining. In line with the hypothesis, overexpression of Otub1 partly rescues Nam-induced MM cell apoptosis, and interestingly, when Otub1 is knocked down, Nam-decreased MM cell survival is also partly ablated, suggesting Otub1 is essential for Nam anti-MM activity. Nam also displays potent anti-MM activity synergistically with Doxorubicin or lenalidomide. In the in vivo assays, Nam almost completely suppresses the growth of MM xenografts in nude mice at low dosages but it shows no toxicity. Given its safety and efficacy, Nam has a potential for MM treatment by targeting the Otub1/c-Maf axis.
Topics: Animals; Cell Line, Tumor; Cysteine Endopeptidases; Ethers; Humans; Mice; Multiple Myeloma; Proto-Oncogene Proteins c-maf; Spiro Compounds
PubMed: 32999280
DOI: 10.1038/s41419-020-03017-4 -
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 -
Acta Neurobiologiae Experimentalis 2022This study was designed to explore the function of lncRNA MAFG‑AS1/miR‑642a‑5p/Notch1 in glioblastoma (GBM) cells under radiation. GBM cells (M059K and M059J) were...
This study was designed to explore the function of lncRNA MAFG‑AS1/miR‑642a‑5p/Notch1 in glioblastoma (GBM) cells under radiation. GBM cells (M059K and M059J) were transfected or/and irradiated. Western blotting was used to detect Notch1 protein and its downstream Hes1 protein. Cell Counting Kit-8 assay and flow cytometry were applied for viability and apoptosis tests, respectively. Luciferase reporter plasmids and Ago2 antibody were used to verify the predicted binding of miR‑642a‑5p to MAFG‑AS1 or Notch1 mRNA. Notch1 and MAFG‑AS1 were highly expressed and miR‑642a‑5p was lowly expressed in radioresistant M059K cells. Knockdown of Notch1 inhibited radioresistance and promoted apoptosis in M059K cells. MAFG‑AS1 competed with Notch1 mRNA for binding of miR‑642a‑5p and therefore promoted the expression of Notch1. Overexpression of miR‑642a‑5p or silencing of MAFG‑AS1 inhibited the radioresistance of M059K cells. Knockdown of Notch1 or overexpression of miR‑642a‑5p reduced viability and increased apoptosis in irradiated M059J cells overexpressing MAFG‑AS1. MAFG‑AS1 reduces the radiosensitivity of GBM cells via miR‑642a‑5p/Notch1 axis.
Topics: Cell Line, Tumor; Cell Proliferation; Glioblastoma; Humans; MafG Transcription Factor; MicroRNAs; RNA, Long Noncoding; RNA, Messenger; Receptor, Notch1; Repressor Proteins
PubMed: 36214714
DOI: 10.55782/ane-2022-030 -
Congenital Anomalies May 2019Development of external genitalia and perineum is the subject of developmental biology as well as toxicology and teratology researches. Cloaca forms in the lower... (Review)
Review
Development of external genitalia and perineum is the subject of developmental biology as well as toxicology and teratology researches. Cloaca forms in the lower (caudal) end of endoderm. Such endodermal epithelia and surrounding mesenchyme interact with various signals to form the external genitalia. External genitalia (the anlage termed as genital tubercle: GT) formation shows prominent sexually dimorphic morphogenesis in late embryonic stages, which is an unexplored developmental research field because of many reasons. External genitalia develop adjacent to the cloaca which develops urethra and corporal bodies. Developmental regulators including growth factor signals are necessary for epithelia-mesenchyme interaction (EMI) in posterior embryos including the cloaca and urethra in the genitalia. In the case of male type urethra, formation of tubular urethra proceeds from the lower (ventral) side of external genitalia as a masculinization process in contrast to the case of female urethra. Mechanisms for its development are not elucidated yet due to the lack of suitable mutant mouse models. Because of the recent progresses of Cre (recombinase)-mediated conditional target gene modification analyses, many developmental regulatory genes become increasingly analyzed. Conditional gene knockout mouse approaches and tissue lineage approaches are expected to offer vital information for such sexually dimorphic developmental processes. This review aims to offer recent updates on the progresses of these emerging developmental processes for the research field of congenital anomalies.
Topics: Animals; Congenital Abnormalities; Disease Models, Animal; Embryo, Mammalian; Endoderm; Female; Gene Expression Regulation, Developmental; Genitalia; Humans; MafB Transcription Factor; Male; Mice; Mice, Knockout; Organogenesis; Perineum; Sex Characteristics; Transcription Factor AP-1; Wnt Signaling Pathway
PubMed: 30554442
DOI: 10.1111/cga.12319 -
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 -
Molecular and Cellular Biology Aug 2022The transcription factor MafB plays an essential role in -cell differentiation during the embryonic stage in rodents. Although MafB disappears from -cells after birth,...
The transcription factor MafB plays an essential role in -cell differentiation during the embryonic stage in rodents. Although MafB disappears from -cells after birth, it has been reported that MafB can be evoked in -cells and is involved in insulin-cell number and islet architecture maintenance in adult mice under diabetic conditions. However, the underlying mechanism by which MafB protects -cells remains unknown. To elucidate this, we performed RNA sequencing using an inducible diabetes model ( mice) that we previously generated. We found that the deletion of can induce -cell dedifferentiation, characterized by the upregulation of dedifferentiation markers, and as well as several -cell-disallowed genes, and by the downregulation of mature -cell markers, and . However, there is no re-expression of well-known progenitor cell markers, and . Further, the appearance of ALDH1A3 cells and the disappearance of UCN3 cells also verify the -cell dedifferentiation state. Collectively, our results suggest that MafB can maintain -cell identity under certain pathological conditions in adult mice, providing novel insight into the role of MafB in -cell identity maintenance.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Diabetes Mellitus; Insulin; Insulin-Secreting Cells; Maf Transcription Factors, Large; MafB Transcription Factor; Mice; Nerve Tissue Proteins
PubMed: 35862726
DOI: 10.1128/mcb.00541-21 -
Cell Death & Disease Nov 2023The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid...
The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.
Topics: Humans; Cell Line; Leukemia, Myeloid, Acute; MafB Transcription Factor; Myeloid-Lymphoid Leukemia Protein; Phenotype; RNA, Small Interfering
PubMed: 37996430
DOI: 10.1038/s41419-023-06276-z -
Gene Aug 2016BACH1 (BTB and CNC homology 1, basic leucine zipper transcription factor 1) is a transcriptional factor and a member of cap 'n' collar (CNC) and basic region leucine... (Review)
Review
BACH1 (BTB and CNC homology 1, basic leucine zipper transcription factor 1) is a transcriptional factor and a member of cap 'n' collar (CNC) and basic region leucine zipper factor family. In contrast to other bZIP family members, BACH1 appeared as a comparatively specific transcription factor. It acts as transcription regulator and is recognized as a recently hypoxia regulator and functions as an inducible repressor for the HO-1 gene in many human cell types in response to stress oxidative. In regard to studies lately, although, BACH1 has been related to the regulation of oxidative stress and heme oxidation, it has never been linked to invasion and metastasis. Recent studies have showed that BACH1 is involved in bone metastasis of breast cancer by up-regulating vital metastatic genes like CXCR4 and MMP1. This newly discovered aspect of BACH1 gene provides new insight into cancer progression study and stands on its master regulator role in metastasis process, raising the possibility of considering it as a potential target for cancer therapy.
Topics: Animals; Basic-Leucine Zipper Transcription Factors; Bone Neoplasms; Breast Neoplasms; Cell Movement; Fanconi Anemia Complementation Group Proteins; Heme Oxygenase-1; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Oxidative Stress; Proto-Oncogene Proteins c-maf
PubMed: 27108804
DOI: 10.1016/j.gene.2016.04.040