PRMT6 activates cyclin D1 expression in conjunction with the transcription factor LEF1.
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ABSTRACT:
SUBMITTER: Schneider L
PROVIDER: S-EPMC8129428 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:MUC1 is a heterodimeric glycoprotein that is overexpressed in breast cancers. The present studies demonstrate that the oncogenic MUC1 C-terminal subunit (MUC1-C) associates with the TCF7L2 transcription factor. The MUC1-C cytoplasmic domain (MUC1-CD) binds directly to the TCF7L2 C-terminal region. MUC1-C blocks the interaction between TCF7L2 and the C-terminal-binding protein (CtBP), a suppressor of TCF7L2-mediated transcription. TCF7L2 and MUC1-C form a complex on the cyclin D1 gene promoter and MUC1-C promotes TCF7L2-mediated transcription by the recruitment of β-catenin and p300. Silencing MUC1-C in human breast cancer cells down-regulated activation of the cyclin D1 promoter and decreased cyclin D1 expression. In addition, a MUC1-C inhibitor blocked the interaction with TCF7L2 and suppressed cyclin D1 levels. These findings indicate that the MUC1-C oncoprotein contributes to TCF7L2 activation and thereby promotes cyclin D1 expression in breast cancer cells.
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Project description:The tight junction protein ZO-1 inhibits G1/S-phase transition by cytoplasmic sequestration of a complex formed by CDK4 and the transcription factor ZONAB. Canine ZONAB is the homologue of human DbpA, an E2F target gene that is overexpressed in different carcinomas. Since the ZONAB target genes that are involved in G1/S-phase transition are unknown, we employed the mammary epithelial cell line MCF-10A and cDNA arrays to screen for such genes. We identified genes encoding cell cycle and replication proteins whose expression was altered due to increased ZONAB expression. For proliferative cell nuclear antigen and cyclin D1 genes, we show that increased mRNA levels resulted in increased protein levels and we identified ZONAB-responsive elements in their promoters by using different approaches, including chromatin immunoprecipitation assays. RNA interference and overexpression of ZONAB affected the proliferation of both MCF-10A and MDCK cells as well as the differentiation of MDCK cells into polarized cysts in three-dimensional cultures. These results indicate that ZONAB regulates the transcription of genes that are important for G1/S-phase progression and links tight junctions to the transcriptional control of key cell cycle regulators and epithelial cell differentiation.
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Project description:BackgroundCoordinated chondrocyte proliferation and differentiation are required for normal endochondral bone growth. Transcription factors binding to the cyclicAMP response element (CRE) are known to regulate these processes. One member of this family, Activating Transcription Factor 3 (ATF3), is expressed during skeletogenesis and acts as a transcriptional repressor, but the function of this protein in chondrogenesis is unknown.ResultsHere we demonstrate that Atf3 mRNA levels increase during mouse chondrocyte differentiation in vitro and in vivo. In addition, Atf3 mRNA levels are increased in response to cytochalasin D treatment, an inducer of chondrocyte maturation. This is accompanied by increased Atf3 promoter activity in cytochalasin D-treated chondrocytes. We had shown earlier that transcription of the cell cycle genes cyclin D1 and cyclin A in chondrocytes is dependent on CREs. Here we demonstrate that overexpression of ATF3 in primary mouse chondrocytes results in reduced transcription of both genes, as well as decreased activity of a CRE reporter plasmid. Repression of cyclin A transcription by ATF3 required the CRE in the cyclin A promoter. In parallel, ATF3 overexpression reduces the activity of a SOX9-dependent promoter and increases the activity of a RUNX2-dependent promoter.ConclusionOur data suggest that transcriptional induction of the Atf3 gene in maturing chondrocytes results in down-regulation of cyclin D1 and cyclin A expression as well as activation of RUNX2-dependent transcription. Therefore, ATF3 induction appears to facilitate cell cycle exit and terminal differentiation of chondrocytes.
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Project description:OBJECTIVES:Control of cell proliferation is critical for accurate cell differentiation and tissue formation, during development and regeneration. Here, we have analysed the role of microphthalmia-associated transcription factor MITF and its direct target, T-box factor TBX2, in regulating proliferation of mammalian neural crest-derived melanocytes. MATERIALS AND METHODS:Immunohistochemistry was used to examine spatial and temporal expression of TBX2 in melanocytes in vivo. RNAi and cell proliferation analysis were used to investigate functional roles of TBX2. Furthermore, quantitative RT-PCR, western blot analysis and flow cytometry were used to further scrutinize molecular mechanisms underlying TBX2-dependent cell proliferation. RESULTS:TBX2 was found to be co-expressed with MITF in melanocytes of mouse hair follicles. Specific Tbx2 knockdown in primary neural crest cells led to inhibition MITF-positive melanoblast proliferation. Tbx2 knockdown in melan-a cells led to reduction in Cyclin D1 expression and G1-phase cell cycle arrest. TBX2 directly activated Ccnd1 transcription by binding to a specific sequence in the Ccnd1 promoter, and the defect in cell proliferation could be rescued partially by overexpression of Cyclin D1 in Tbx2 knockdown melanocytes. CONCLUSIONS:Results suggest that the Mitf-Tbx2-Cyclin D1 pathway played an important role in regulation of melanocyte proliferation, and provided novel insights into the complex physiology of melanocytes.
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Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is the most difficult subtype of esophageal cancer to treat due to the paucity of effective targeted therapy. ESCC is believed to arise from cancer stem cells (CSCs) that contribute to metastasis and chemoresistance. Despite advances in diagnosis and treatment, the prognosis of ESCC patients remains poor.MethodsIn this study, we applied western blot, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry, RNA-Seq analysis, luciferase reporter assay, Chip-qPCR, bioinformatics analysis, and a series of functional assays to show the potential role of LEF1 in regulating esophageal CSCs.ResultsWe found that the overexpression of LEF1 was associated with aberrant clinicopathological characteristics and the poor prognosis of ESCC patients. In addition, the elevated expression of LEF1 and OV6 was significantly associated with aberrant clinicopathological features, and poor patient prognosis. Moreover, the overexpression of LEF1 was observed in esophageal CSCs purified by the magnetic sorting of adherent and spheroidal ESCC cells. The increased level of LEF1 in CSCs facilitated the expression of CSC markers, stem cell-like properties, resistance to chemotherapy, and tumorigenicity and increased the percentage of CSCs in ESCC samples. Conversely, the knockdown of LEF1 significantly diminished the self-renewal properties of ESCC. We showed that LEF1 played an important mechanical role in activating the TGF-β signaling pathway by directly binding to the ID1 gene promoter. A positive association between LEF1 and ID1 expression was also observed in clinical ESCC samples.ConclusionOur results indicate that the overexpression of LEF1 promotes a CSC-like phenotype in and the tumorigenicity of ESCC by activating the TGF-β signaling pathway. The inhibition of LEF1 might therefore be a novel therapeutic target to inactivate CSCs and inhibit tumor progression.
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Project description:We have used a continuous fluorescence monitoring method to assess cyclin D1 mRNA expression in a variety of hematological and non-hematological processes. We examined 14 cell lines, 11 reactive lymphoid tissues, and 57 primary hematopoietic neoplasms including mantle cell lymphoma (MCL) (n = 10), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (n = 11), acute lymphoblastic leukemia/lymphoma (n = 15), follicular lymphoma (n = 6), peripheral T-cell lymphoma (PTCL) (n = 3), anaplastic large cell lymphoma (n = 3), hairy cell leukemia (n = 3), Burkitt lymphoma (n = 1), Burkitt-like lymphoma (n = 4), and plasmacytoma (n = 1) for the expression of cyclin D1 mRNA using fluorescently labeled sequence-specific hybridization probes. Fluorescence (F) was plotted against cycle (C) number over 45 cycles. The log-linear portion of the F versus C graph identified a fractional cycle number for threshold fluorescence. A beta-globin mRNA transcript with equivalent amplification efficiency to that of cyclin D1 was used for assessment of RNA integrity and normalization. In general, the MCLs demonstrated substantially higher levels of cyclin D1 mRNA than the other lymphoproliferative processes. Moderately high levels of cyclin D1 mRNA were detected in one PTCL. On average, the CLL/SLL cases showed cyclin D1 mRNA levels two to three orders of magnitude lower than observed in the MCLs. Cell lines derived from non-hematopoietic neoplasms such as fibrosarcoma, small cell carcinoma, and neuroblastoma showed comparable or higher levels of cyclin D1 mRNA than the MCLs. Our results indicate that quantitative real-time reverse transcription (RT) polymerase chain reaction is a simple, rapid, and accurate technique for assessing cyclin D1 expression, and while it is not specific, it can reliably be used in the distinction of MCL from CLL/SLL.
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Project description:Analysis of mammary glands from tet-inducible(rtTA) transgenic mice expressing cyclin D1 using Affymetrix Mouse Gene 1.0 ST GeneChip arrays. MMTV-rtTA transgenic mice (MMTV-Mouse Mammary Tumor Virus promoter) were cross-mated to cyclin D1 transgenic mice under control of tet operon. 8-week-old tetracycline-inducible cyclin D1/rtTA bi-transgenic pregnant female mice (12 days postcoitus) were treated with doxycycline through drinking water supplementation at a final concentration of 2 mg/ml. Control mice were rtTA transgenics alone and treated in the same manner. After 7 days of doxycycline treatment, the mice were sacrificed and mammary glands taken for RNA isolation. Results provide insight into the in vivo gene expression pattern regulated by cyclin D1 through acute induction. Analysis of mammary glands from MMTV-cyclin D1/WT and MMTV-cyclin D1/KE using Affymetrix Mouse 430A v2.0 GeneChip arrays. Cyclin D1 point mutant, cyclin D1/KE K112E (K112E) contains a lysine to glutamine substitution at amino acid position 112. cyclin D1. The cyclin D1/KE mutant fails to induce cyclin D1-dependent kinase activity. Female MFD1, MFD1-KE, and WT mice were monitored twice weekly, up to 760 days, for the development of palpable tumors. Those developing palpable tumors were sacrificed within a week of tumor detection. Tumors were dissected and portions snap frozen for RNA isolation. Results provide insight into the in vivo gene expression pattern regulated by cyclin D1 that is kinase independent.
2013-12-31 | GSE43216 | GEO
Project description:The causative gene of Fukuyama congenital muscular dystrophy (fukutin) is involved in formation of the basement membrane through glycosylation of alpha-dystroglycan. However, there are other proposed functions that have not been fully understood. Using cultured astrocytes (1321N1), we found nuclear localization of fukutin and a positive relationship between fukutin expression and cell proliferation. Among potential proteins regulating cell proliferation, we focused on cyclin D1, by reverse-transcription polymerase chain reaction, Western blotting, immunocytochemistry, enzyme-linked immunosorbent assay (ELISA), and sandwich ELISA. Expression of cyclin D1 was significantly downregulated by fukutin knockdown and significantly upregulated by fukutin overexpression. Moreover, fukutin was proven to bind to the activator protein-1 (AP-1) binding site of cyclin D1 promoter, as well as the AP-1 component c-Jun. The c-Jun phosphorylation status was not significantly influenced by knockdown or overexpression of fukutin. The present results provide in vitro evidence for a novel function of fukutin, which participates in cell proliferation by enhancing cyclin D1 expression through forming a complex with AP-1. It is likely that fukutin is a potential cofactor of AP-1.
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Project description:D-Cyclins control progression through the G1 phase and the G1/S transition of the cell cycle. In the adult brain, they regulate neurogenesis which is limited to the sub-granular zone of the dentate gyrus (DG) and to the sub-ventricular zone (SVZ) of the lateral ventricles. Yet, D-cyclins have also been detected in other parts of the adult brain in differentiated neurons that do not proliferate and rather die by apoptosis in response to cell cycle reactivation. Expression of D-cyclins in astrocytes has also been reported but published results, such as those concerning neurons, appear conflictual. We carried out this study in order to clarify the general pattern of D-cyclin expression in the mouse brain. By performing GFAP/cyclin-D1 double labeling experiments, we detected hypertrophic astrocytes expressing cyclin-D1 in their cytoplasmic processes. Their number increased with age in the hippocampus area but decreased with age in the SVZ. Clusters of astrocytes expressing cyclin-D1 were also detected in the cortical areas of old mice and around blood vessels of neurogenic areas. Other non-asteroidal small cells, probably stem cells, expressed both GFAP and nuclear cyclin-D1 in the neurogenic area of the DG and in the SVZ at a higher density in young mice than in old mice. Finally, cells expressing cyclin-D1 but not GFAP were also found scattered in the striatum and the CA1 region of the hippocampus, and at a high percentage in cortical layers of young and old mice. Our results suggest that astrocytes may control neuronal functions and proliferation by modulating, in normal or altered conditions such as aging or degenerative diseases, cyclin-D1 expression.
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