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Blood Mar 2021The oncogenic transcription factor c-Maf has been proposed as an ideal therapeutic target for multiple myeloma (MM), but how to achieve it is still elusive. In the...
The oncogenic transcription factor c-Maf has been proposed as an ideal therapeutic target for multiple myeloma (MM), but how to achieve it is still elusive. In the present study, we found the Otub1/c-Maf axis could be a potential target. Otub1, an OTU family deubiquitinase, was found to interact with c-Maf by mass spectrometry. Otub1 abrogates c-Maf K48-linked polyubiquitination, thus preventing its degradation and enhancing its transcriptional activity. Specifically, this deubiquitinating activity depends on its Lys71 and the N terminus but is independent of UBE2O, a known E2 of c-Maf. Otub1 promotes MM cell survival and MM tumor growth. In contrast, silence of Otub1 leads to c-Maf degradation and c-Maf-expressing MM cell apoptosis. Therefore, the Otub1/c-Maf axis could be a therapeutic target of MM. In order to explore this concept, we performed a c-Maf recognition element-driven luciferase-based screen against US Food and Drug Administration-approved drugs and natural products, from which the generic cardiac glycoside lanatoside C (LanC) is found to prevent c-Maf deubiquitination and induces its degradation by disrupting the interaction of Otub1 and c-Maf. Consequently, LanC inhibits c-Maf transcriptional activity, induces c-Maf-expressing MM cell apoptosis, and suppresses MM growth and prolongs overall survival of model mice, but without apparent toxicity. Therefore, the present study identifies Otub1 as a novel deubiquitinase of c-Maf and establishes that the Otub1/c-Maf axis is a potential therapeutic target for MM.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Deubiquitinating Enzymes; Drug Discovery; HEK293 Cells; Humans; Mice, Inbred BALB C; Mice, Nude; Multiple Myeloma; Protein Interaction Maps; Proto-Oncogene Proteins c-maf; Signal Transduction; Ubiquitination; Mice
PubMed: 32842143
DOI: 10.1182/blood.2020005199 -
Science Immunology Mar 2024T follicular helper (T) cells are essential for effective antibody responses, but deciphering the intrinsic wiring of mouse T cells has long been hampered by the lack of...
T follicular helper (T) cells are essential for effective antibody responses, but deciphering the intrinsic wiring of mouse T cells has long been hampered by the lack of a reliable protocol for their generation in vitro. We report that transforming growth factor-β (TGF-β) induces robust expression of T hallmark molecules CXCR5 and Bcl6 in activated mouse CD4 T cells in vitro. TGF-β-induced mouse CXCR5 T cells are phenotypically, transcriptionally, and functionally similar to in vivo-generated T cells and provide critical help to B cells. The study further reveals that TGF-β-induced CXCR5 expression is independent of Bcl6 but requires the transcription factor c-Maf. Classical TGF-β-containing T helper 17 (T17)-inducing conditions also yield separate CXCR5 and IL-17A-producing cells, highlighting shared and distinct cell fate trajectories of T and T17 cells. We demonstrate that excess IL-2 in high-density T cell cultures interferes with the TGF-β-induced T cell program, that T and T17 cells share a common developmental stage, and that c-Maf acts as a switch factor for T versus T17 cell fates in TGF-β-rich environments in vitro and in vivo.
Topics: Animals; Mice; T-Lymphocytes, Helper-Inducer; Transforming Growth Factor beta; B-Lymphocytes; CD4-Positive T-Lymphocytes; Cell Differentiation; Proto-Oncogene Proteins c-maf
PubMed: 38427718
DOI: 10.1126/sciimmunol.add4818 -
Nature Cell Biology Dec 2023MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications....
MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications. Oestrogen-receptor-positive (ER) BCa requires oestrogen for both growth and metastasis, albeit by ill-known mechanisms. Here we integrate proteomics, transcriptomics, epigenomics, chromatin accessibility and functional assays from human and syngeneic mouse BCa models to show that MAF directly interacts with oestrogen receptor alpha (ERα), thereby promoting a unique chromatin landscape that favours metastatic spread. We identify metastasis-promoting genes that are de novo licensed following oestrogen exposure in a MAF-dependent manner. The histone demethylase KDM1A is key to the epigenomic remodelling that facilitates the expression of the pro-metastatic MAF/oestrogen-driven gene expression program, and loss of KDM1A activity prevents this metastasis. We have thus determined that the molecular basis underlying MAF/oestrogen-mediated metastasis requires genetic, epigenetic and hormone signals from the systemic environment, which influence the ability of BCa cells to metastasize.
Topics: Animals; Female; Humans; Mice; Breast Neoplasms; Cell Line, Tumor; Chromatin; Epigenesis, Genetic; Estrogen Receptor alpha; Estrogens; Histone Demethylases; Gene Amplification; Proto-Oncogene Proteins c-maf
PubMed: 37945904
DOI: 10.1038/s41556-023-01281-y -
Biochimica Et Biophysica Acta. Gene... Apr 2018As a master regulator of transcription by RNA polymerase (Pol) III, Maf1 represses the synthesis of highly abundant non-coding RNAs as anabolic signals dissipate, as the... (Review)
Review
As a master regulator of transcription by RNA polymerase (Pol) III, Maf1 represses the synthesis of highly abundant non-coding RNAs as anabolic signals dissipate, as the quality or quantity of nutrients decreases, and under a wide range of cellular and environmental stress conditions. Thus, Maf1 responds to changes in cell physiology to conserve metabolic energy and to help maintain appropriate levels of tRNAs and other essential non-coding RNAs. Studies in different model organisms and cell-based systems show that perturbations of Maf1 can also impact cell physiology and metabolism. These effects are mediated by changes in Pol III transcription and/or by effects of Maf1 on the expression of select Pol II-transcribed genes. Maf1 phenotypes can vary between different systems and are sometimes conflicting as in comparisons between Maf1 KO mice and cultured mammalian cells. These studies are reviewed in an effort to better appreciate the relationship between Maf1 function and cell physiology. This article is part of a Special Issue entitled: SI: Regulation of tRNA synthesis and modification in physiological conditions and disease edited by Dr. Boguta Magdalena.
Topics: Animals; Caenorhabditis elegans Proteins; Energy Metabolism; Gene Expression Regulation; Gene Expression Regulation, Fungal; Gluconeogenesis; MafB Transcription Factor; Mammals; Mice; Mice, Knockout; Mitochondria; Models, Molecular; Phenotype; Protein Conformation; RNA Polymerase III; Repressor Proteins; Saccharomyces cerevisiae Proteins; Transcription Factors; Transcription, Genetic
PubMed: 29248739
DOI: 10.1016/j.bbagrm.2017.11.009 -
Archives of Insect Biochemistry and... Jun 2020Insects have evolved resistance to almost all insecticides developed for their control. Multiple mechanisms of resistance, including enhanced metabolism and excretion of... (Review)
Review
Insects have evolved resistance to almost all insecticides developed for their control. Multiple mechanisms of resistance, including enhanced metabolism and excretion of insecticides, target-site insensitivity, reduced penetration of insecticides, and avoidance behavior, have been reported. The genes coding for proteins involved in resistance have been identified in numerous insects. The enzymes and transporters required for all three phases of insecticide metabolism and excretion including cytochrome P450 monooxygenases, glutathione S-transferases, UDP-glucuronosyltransferases, carboxylesterases, and ATP-binding cassette transmembrane transporters have been identified. Recent research in multiple insect species identified CNC-bZIP transcription factor superfamily members as regulators of genes coding for enzymes and transporters involved in insecticide metabolic resistance. The information on the pathway including reactive oxygen species, cap "n" collar isoform-C, and its heterodimer partner, muscle aponeurosis fibromatosis transcription factors involved in overexpression of enzymes and transporters involved insecticide resistance will be summarized.
Topics: Animals; Inactivation, Metabolic; Insect Proteins; Insecta; Insecticide Resistance; Insecticides; Oncogene Protein v-maf; Transcription Factors
PubMed: 32281173
DOI: 10.1002/arch.21674 -
European Journal of Medical Research Nov 2023Long noncoding RNAs (lncRNAs) refer to a type of non-protein-coding transcript of more than 200 nucleotides. LncRNAs play fundamental roles in disease development and... (Review)
Review
Long noncoding RNAs (lncRNAs) refer to a type of non-protein-coding transcript of more than 200 nucleotides. LncRNAs play fundamental roles in disease development and progression, and lncRNAs are dysregulated in many pathophysiological processes. Thus, lncRNAs may have potential value in clinical applications. The lncRNA, MAF BZIP Transcription Factor G (MAFG)-AS1, is dysregulated in several cancer, including breast cancer, lung cancer, liver cancer, bladder cancer, colorectal cancer, gastric cancer, esophagus cancer, prostate cancer, pancreatic cancer, ovarian cancer, and glioma. Altered MAFG-AS1 levels are also associated with diverse clinical characteristics and patient outcomes. Mechanistically, MAFG-AS1 mediates a variety of cellular processes via the regulation of target gene expression. Therefore, the diagnostic, prognostic, and therapeutic aspects of MAFG-AS1 have been widely explored. In this review, we discuss the expression, major roles, and molecular mechanisms of MAFG-AS1, the relationship between MAFG-AS1 and clinical features of diseases, and the clinical applications of MAFG-AS1.
Topics: Male; Humans; RNA, Long Noncoding; MicroRNAs; Lung Neoplasms; Breast Neoplasms; Prognosis; Gene Expression Regulation, Neoplastic; Cell Proliferation; Cell Line, Tumor; Repressor Proteins; MafG Transcription Factor
PubMed: 37941063
DOI: 10.1186/s40001-023-01486-9 -
Trends in Cancer Apr 2023In innate immune cells, the transcription factor cellular musculoaponeurotic fibrosarcoma (c-Maf) influences cell fate and function through molecular and metabolic...
In innate immune cells, the transcription factor cellular musculoaponeurotic fibrosarcoma (c-Maf) influences cell fate and function through molecular and metabolic programming, thereby influencing immune homeostasis and antitumor immunity. We discuss recent c-Maf landmark discoveries with a focus on the immunosuppressive tumor microenvironment (TME) and provide a new perspective on c-Maf-targeted cancer immunotherapy.
Topics: Humans; Fibrosarcoma; Gene Expression Regulation; Immunotherapy; Macrophages; Transcription Factors; Tumor Microenvironment
PubMed: 36564282
DOI: 10.1016/j.trecan.2022.12.002 -
Molecular Biology Reports Jan 2020AP-1 is a dimeric complex that is composed of JUN, FOS, ATF and MAF protein families. FOS-related antigen 1 (FRA1) which encoded by FOSL1 gene, belongs to the FOS... (Review)
Review
AP-1 is a dimeric complex that is composed of JUN, FOS, ATF and MAF protein families. FOS-related antigen 1 (FRA1) which encoded by FOSL1 gene, belongs to the FOS protein family, and mainly forms an AP-1 complex with the protein of the JUN family to exert an effect. Regulation of FRA1 occurs at levels of transcription and post-translational modification, and phosphorylation is the major post-translational modification. FRA1 is mainly regulated by the mitogen-activated protein kinases signaling pathway and is degraded by ubiquitin-independent proteasomes. FRA1 can affect biological functions, such as tumor proliferation, differentiation, invasion and apoptosis. Studies have demonstrated that FRA1 is abnormally expressed in many tumors and plays a relevant role, but the specific condition varies from the target organs. FRA1 is overexpressed in breast cancer, lung cancer, colorectal cancer, prostate cancer, nasopharyngeal cancer, thyroid cancer and other tumors. However, the expression of FRA1 is decreased in cervical cancer, and the expression of FRA1 in ovarian cancer and oral squamous cell carcinoma is still controversial. In this review, we present a detailed description of the regulatory factors and functions of FRA1, also, the expression of FRA1 in various tumors and its function in relative tumor.
Topics: Female; Gene Expression Regulation, Neoplastic; Humans; Male; MicroRNAs; Neoplasms; Proto-Oncogene Proteins c-fos; Transcription Factor AP-1
PubMed: 31612408
DOI: 10.1007/s11033-019-05123-9 -
World Journal of Diabetes Feb 2015The Maf family of transcription factors is characterized by a typical bZip structure; these transcription factors act as important regulators of the development and... (Review)
Review
The Maf family of transcription factors is characterized by a typical bZip structure; these transcription factors act as important regulators of the development and differentiation of many organs and tissues, including the kidney. The Maf family consists of two subgroups that are characterized according to their structure: large Maf transcription factors and small Maf transcription factors. The large Maf subgroup consists of four proteins, designated as MAFA, MAFB, c-MAF and neural retina-specific leucine zipper. In particular, MAFA is a distinct molecule that has been attracting the attention of researchers because it acts as a strong transactivator of insulin, suggesting that Maf transcription factors are likely to be involved in systemic energy homeostasis. In this review, we focused on the regulation of glucose/energy balance by Maf transcription factors in various organs.
PubMed: 25685288
DOI: 10.4239/wjd.v6.i1.175 -
Biomarker Research Feb 2023The Maf proteins (Mafs) belong to basic leucine zipper transcription factors and are members of the activator protein-1 (AP-1) superfamily. There are two subgroups of... (Review)
Review
The Maf proteins (Mafs) belong to basic leucine zipper transcription factors and are members of the activator protein-1 (AP-1) superfamily. There are two subgroups of Mafs: large Mafs and small Mafs, which are involved in a wide range of biological processes, such as the cell cycle, proliferation, oxidative stress, and inflammation. Therefore, dysregulation of Mafs can affect cell fate and is closely associated with diverse diseases. Accumulating evidence has established both large and small Mafs as mediators of tumor development. In this review, we first briefly describe the structure and physiological functions of Mafs. Then we summarize the upstream regulatory mechanisms that control the expression and activity of Mafs. Furthermore, we discuss recent studies on the critical role of Mafs in cancer progression, including cancer proliferation, apoptosis, metastasis, tumor/stroma interaction and angiogenesis. We also review the clinical implications of Mafs, namely their potential possibilities and limitations as biomarkers and therapeutic targets in cancer.
PubMed: 36750911
DOI: 10.1186/s40364-023-00457-w