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International Journal of Molecular... Nov 2015Protein transduction using cell-penetrating peptides (CPPs) is useful for the delivery of large protein molecules, including some transcription factors. This method is... (Review)
Review
Protein transduction using cell-penetrating peptides (CPPs) is useful for the delivery of large protein molecules, including some transcription factors. This method is safer than gene transfection methods with a viral vector because there is no risk of genomic integration of the exogenous DNA. Recently, this method was reported as a means for the induction of induced pluripotent stem (iPS) cells, directing the differentiation into specific cell types and supporting gene editing/correction. Furthermore, we developed a direct differentiation method to obtain a pancreatic lineage from mouse and human pluripotent stem cells via the protein transduction of three transcription factors, Pdx1, NeuroD, and MafA. Here, we discuss the possibility of using CPPs as a means of directing the differentiation of iPS cells and other stem cell technologies.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Cell-Penetrating Peptides; Cellular Reprogramming; Cinnamates; Gene Expression; Glucagon-Like Peptide 1; Homeodomain Proteins; Humans; Induced Pluripotent Stem Cells; Insulin-Secreting Cells; Intercellular Signaling Peptides and Proteins; Maf Transcription Factors, Large; Mice; Nerve Tissue Proteins; Niacinamide; Trans-Activators; Tretinoin; Veratrum Alkaloids
PubMed: 26561805
DOI: 10.3390/ijms161125986 -
Archives of Pharmacal Research Mar 2020Cellular detoxication is essential for health because it provides protection against various chemicals and xenobiotics. The KEAP1-NRF2 system is important for cellular... (Review)
Review
Cellular detoxication is essential for health because it provides protection against various chemicals and xenobiotics. The KEAP1-NRF2 system is important for cellular defense against oxidative and electrophilic stresses as NRF2 activates the transcription of an array of cytoprotective genes, including drug-metabolizing and antioxidant enzymes, in a stress-dependent manner. The CNC family of transcription factors, including NRF2, form heterodimers with small Maf (sMaf) proteins and bind to consensus DNA sequences that have been referred to as antioxidant response element, electrophile response element, or NF-E2-binding element. These sequences are now collectively called CNC-sMaf binding element (CsMBE). In addition to forming a heterodimer with CNC proteins, sMaf proteins can form homodimers and recognize regulatory motifs called Maf recognition element (MARE). Although the CsMBE sequence substantially overlaps with that of MARE, the sequences differ. NRF2 selectively recognizes CsMBE, which is critical for cytoprotection. Recent advances in high-throughput sequencing and population-scale genome analysis provide new insights into the transcriptional regulation involved in the stress response. The integration of a genome-wide map of NRF2 occupancy with disease-susceptibility loci reveals the associations between polymorphisms in CsMBE and disease risk, information useful for the personalized medicine of the future.
Topics: Animals; Binding Sites; Enhancer Elements, Genetic; Hearing Loss, Noise-Induced; Humans; Lung Neoplasms; Maf Transcription Factors, Small; NF-E2-Related Factor 2; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive
PubMed: 31792803
DOI: 10.1007/s12272-019-01193-2 -
Cell Reports Oct 2023T cell receptor (TCR) Vγ4-expressing γδ T cells comprise interferon γ (IFNγ)- and interleukin-17 (IL-17)-producing effector subsets, with a preference for IL-17...
T cell receptor (TCR) Vγ4-expressing γδ T cells comprise interferon γ (IFNγ)- and interleukin-17 (IL-17)-producing effector subsets, with a preference for IL-17 effector fate decisions during early ontogeny. The existence of adult-thymus-derived IL-17 T cells (γδ17) remains controversial. Here, we use a mouse model in which T cells are generated exclusively in the adult thymus and employ single-cell chromatin state analysis to study their development. We identify adult-thymus-derived Vγ4 T cells that have all the molecular programs to become IL-17 producers. However, they have reduced IL-17 production capabilities and rarely reach the periphery. Moreover, this study provides high-resolution profiles of Vγ4 T cells in the adult thymus and lymph nodes and identifies Zeb1 as a potential γδ17 cell regulator. Together, this study provides valuable insights into the developmental traits of Vγ4 T cells during adulthood and supports the idea of age-specific signals required for thymic export and/or peripheral maturation of γδ17 cells.
Topics: Mice; Animals; Interleukin-17; Receptors, Antigen, T-Cell, gamma-delta; Nuclear Receptor Subfamily 1, Group F, Member 3; Mice, Inbred C57BL; T-Lymphocytes; Thymus Gland; T-Lymphocyte Subsets; Proto-Oncogene Proteins c-maf
PubMed: 37815917
DOI: 10.1016/j.celrep.2023.113230 -
JCI Insight Aug 2023Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet β cells, characterized by inappropriate production of other islet...
Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet β cells, characterized by inappropriate production of other islet cell-enriched hormones. Here, we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin+ (Gast+) cells generated under conditions of chronic hyperglycemia and obesity. A human β cell line deficient in MAFB, but not one lacking MAFA, also produced a GAST+ gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a potentially novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively. Here, we discuss the possibility that induction of Gast/GAST and other non-β cell hormones, by reduction in the levels of these transcription factors, represents a dysfunctional β cell signature.
Topics: Adult; Humans; Animals; Mice; MafB Transcription Factor; Diabetes Mellitus, Type 2; Islets of Langerhans; Insulin-Secreting Cells; Insulin
PubMed: 37606041
DOI: 10.1172/jci.insight.166386 -
Clinical Lymphoma, Myeloma & Leukemia Sep 2019In this study, we analyzed the frequency, clinical characteristics, and prognosis of MAF deletion in Chinese patients with multiple myeloma (MM).
BACKGROUND
In this study, we analyzed the frequency, clinical characteristics, and prognosis of MAF deletion in Chinese patients with multiple myeloma (MM).
PATIENTS AND METHODS
Two hundred consecutive patients with newly diagnosed MM were analyzed. Patient samples were evaluated using a fluorescence in situ hybridization probe set, including 13q deletion, 17p deletion, and 1q21 gain, as well as immunoglobulin heavy chain gene (IgH) rearrangement, IgH/cyclin D1, IgH/fibroblast growth factor receptor 3 (FGFR3), and IgH/MAF. The frequency of MAF deletion and the clinical characteristics and overall survival of patients with MAF deletion were analyzed.
RESULTS
The incidence rate of MAF deletion was 15.0% (30/200) in newly diagnosed patients and all of them were monoallelic of MAF deletion. MAF deletion was associated with sex (P = .008), lactate dehydrogenase level (P = .026), 13q deletion (P = .028), FGFR3 deletion (P = .006), and IgH deletion (P = .018). Additionally, in an analysis of the overall survival rates of patients with MAF deletion who received a bortezomib-based regimen treatment, no significant differences were found in overall survival between positive and negative groups (P = .365).
CONCLUSION
MAF deletion was more frequent than MAF translocation with IgH in patients with MM and was more commonly observed in women. Moreover, MAF deletion was often combined with 13q, FGFR3, and IgH deletion. MAF deletion did not influence prognosis in patients with MM who were given a bortezomib-based chemotherapy regimen.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Bortezomib; Chromosome Aberrations; Chromosome Deletion; Female; Gene Deletion; Gene Rearrangement; Genetic Association Studies; Genetic Predisposition to Disease; Humans; In Situ Hybridization, Fluorescence; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prognosis; Proto-Oncogene Proteins c-maf; Treatment Outcome
PubMed: 31262667
DOI: 10.1016/j.clml.2019.05.016 -
Biochimica Et Biophysica Acta. Gene... Apr 2018The synthesis of transfer RNA (tRNA) is directed by RNA polymerase III (Pol III) specialized in high-level transcription of short DNA templates. Pol III recruitment to... (Review)
Review
The synthesis of transfer RNA (tRNA) is directed by RNA polymerase III (Pol III) specialized in high-level transcription of short DNA templates. Pol III recruitment to tRNA genes is controlled by two general initiation factors, TFIIIB and TFIIIC. They are multi-protein complexes regulated at the level of expression of individual subunits, as well as through phosphorylation and interaction with partner proteins. Here, we describe particular aspects of TFIIIB and TFIIIC control in yeast and human cells. Under stress conditions, tRNA synthesis is negatively regulated by the MAF1 protein, which interacts directly with Pol III. Sequence and function of MAF1 are conserved among eukaryotic organisms from yeast to humans. MAF1 is a phosphoprotein which mediates diverse regulatory signals to Pol III. Interestingly, there is a subset of housekeeping tRNA genes, both in the yeast and human genome, which are less sensitive to MAF1-dependent repression. The possible mechanisms responsible for this differential regulation of tRNA synthesis by MAF1 are discussed.
Topics: Animals; Gene Expression Regulation; Gene Expression Regulation, Fungal; Humans; Maf Transcription Factors; Mammals; Mice; Phosphorylation; Protein Processing, Post-Translational; RNA Polymerase II; RNA Polymerase III; RNA, Transfer; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Transcription Factor TFIIIB; Transcription Factors, TFIII; Transcription, Genetic
PubMed: 29378333
DOI: 10.1016/j.bbagrm.2018.01.011 -
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 -
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 -
International Journal of Molecular... Apr 2022Pancreatic β-cells are specialized to properly regulate blood glucose. Maintenance of the mature β-cell phenotype is critical for glucose metabolism, and β-cell... (Review)
Review
Pancreatic β-cells are specialized to properly regulate blood glucose. Maintenance of the mature β-cell phenotype is critical for glucose metabolism, and β-cell failure results in diabetes mellitus. Recent studies provide strong evidence that the mature phenotype of β-cells is maintained by several transcription factors. These factors are also required for β-cell differentiation from endocrine precursors or maturation from immature β-cells during pancreatic development. Because the reduction or loss of these factors leads to β-cell failure and diabetes, inducing the upregulation or inhibiting downregulation of these transcription factors would be beneficial for studies in both diabetes and stem cell biology. Here, we discuss one such factor, i.e., the transcription factor MAFA. MAFA is a basic leucine zipper family transcription factor that can activate the expression of insulin in β-cells with PDX1 and NEUROD1. MAFA is indeed indispensable for the maintenance of not only insulin expression but also function of adult β-cells. With loss of MAFA in type 2 diabetes, β-cells cannot maintain their mature phenotype and are dedifferentiated. In this review, we first briefly summarize the functional roles of MAFA in β-cells and then mainly focus on the molecular mechanism of cell fate conversion regulated by MAFA.
Topics: Cell Differentiation; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin-Secreting Cells; Maf Transcription Factors, Large
PubMed: 35562869
DOI: 10.3390/ijms23094478 -
The Journal of Clinical Investigation Apr 2020Tumor-associated macrophages (TAMs) represent the most abundant hematopoietic cell type in the solid tumor microenvironment. TAMs drive T cell inhibition, promote...
Tumor-associated macrophages (TAMs) represent the most abundant hematopoietic cell type in the solid tumor microenvironment. TAMs drive T cell inhibition, promote angiogenesis, and produce tumor growth factors. Although they can paradoxically exert antitumor activity and prime protective immunity, the pathways driving this phenotype remain unclear. In this issue of the JCI, Liu and colleagues identified the c-Maf transcription factor as a master regulator of protumoral TAM polarization. The authors found that c-Maf promoted TAMs' immunosuppressive activity, governed their metabolic programming, and drove expression of the macrophage differentiation protein, CSF1R. Further, inhibiting c-Maf in myeloid progenitors, and consequent myeloid-lineage cells, including TAMs, delayed tumor growth. Importantly, β-glucan treatment reduced c-MAF expression in macrophages and monocytes from patients with non-small cell lung cancer (NSCLC) where c-MAF is overexpressed. These results reveal mechanisms whereby myeloid cells drive human cancer progression by thwarting protective immunity and could lead to immunotherapy for most solid malignancies.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Macrophages; MafF Transcription Factor; Tumor Microenvironment
PubMed: 32175921
DOI: 10.1172/JCI135444