A-485 induce significant decrease in MITF and MITF signature genes in melanoma cell lines.
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ABSTRACT:
PROVIDER: PRJNA478559 | ENA |
REPOSITORIES: ENA
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Project description:Differential response to p300 inhibitor A-485 was observed in a panel of melanoma cell lines. Three melanoma cell lines were treated with A-485 and microarray was used to determine gene expession changes at 6 and 24 hours.
2018-12-27 | GSE116459 | GEO
Project description:We evaluated two matched human cell lines derived from primary melanocytes, termed pmel+BRAF(V600E) and pmel+BRAF(V600E)+MITF. These cells are therefore isogenic with the exception of the expression of MITF. Gene Set Enrichment Analysis of microarray data identified a highly significant induction of oxidative phosphorylation gene set in MITF expressing cells compared to control cells.
2013-03-07 | E-GEOD-38007 | biostudies-arrayexpress
Project description:We identified a novel germline mutation of the microphthalmia-associated transcription factor (MITF - E318K). This mutation was found to be present in numerous melanoma families, as well as the general population, where its association with melanoma has a significant effect. We determined the effect of the E318K mutation on global MITF target gene transcription. We developed a tetracycline-inducible system for expression of wild type MITF or the E318K variant in melanoma cell lines with constitutively low or undetectable levels of endogenous MITF (HT144 and C32). We examined whole-genome expression profiles in these cells following induction of either wild-type or E318K MITF for 48 hours. Analysis suggests that the MITF E318K mutant exhibits differential transcriptional activity against some, though not all, target genes. Expression profiling by array
2011-12-01 | E-GEOD-31269 | biostudies-arrayexpress
Project description:MITF, a basic-Helix-Loop-Helix Zipper (bHLHZip) transcription factor, plays vital roles in melanocyte development and functions as an oncogene. We performed a genetic screen for suppressors of the Mitf-associated pigmentation phenotype in mice and identified an intragenic Mitf mutation that terminates MITF at the K316 SUMOylation site, leading to loss of the C-end intrinsically disordered region (IDR). The resulting protein is more nuclear but less stable than wild-type MITF and retains DNA-binding ability. Interestingly, as a dimer, it can translocate wild-type and mutant MITF partners into the nucleus, improving its own stability thus ensuring nuclear MITF supply. To further understand the effect of the suppressor mutation (MITF-sl), we performed CUT&RUN experiments to determine how MITF-sl affects the genome-wide occupancy of MITF. MITF-sl had a higher number of peaks than MITF-WT, with 10,636 peaks (p<0.01) exhibiting statistically significant differences (p < 0.01) between MITF-WT and MITF-sl. Gene ontology analysis indicates that the peaks significantly different between MITF-WT and MITF-sl are associated with genes involved in axonogenesis, axon development, cell growth, and positive regulation of MAPK cascade biological pathways. Our results suggest that the 316-419 domain is critical for selective genome occupancy and transcriptional activation of MITF.
2024-11-06 | GSE267956 | GEO
Project description:Coemansia sp. RSA 485 Resequencing genome sequencing
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Project description:Rhizobium leguminosarum SEMIA 485 genome sequencing
| PRJNA581080 | ENA
Project description:Histone modifications, largely regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) have been recognized as major regulatory mechanisms governing human diseases including cancer. Despite significant effort and recent advances, the mechanism by which the p300 transcriptional coactivator mediates tumorigenesis remains unclear. Here, we use a genetic and chemical approach to identify the Microphthalmia-associated transcription factor (MITF) as a critical downstream target of p300 driving human melanoma growth. We find that direct transcriptional control of MITF by p300-dependent histone acetylation within proximal gene regulatory regions is coupled to cellular proliferation, suggesting a significant growth regulatory axis. Further analysis revealed Forkhead Box M1 (FOXM1) as a key effector of the p300-MITF axis driving cell growth, which is selectively activated in human melanomas. Targeted chemical inhibition of p300 histone acetyltransferase activity using a potent and selective catalytic p300/CBP inhibitor confirmed the critical role of the p300-MITF-FOXM1 axis in melanoma and demonstrated significant growth inhibitory effects in melanoma cells expressing high levels of MITF. These data support p300 as a promising novel epigenetic therapeutic target in human melanoma.
2020-03-22 | GSE128737 | GEO
Project description:The close integration of the MAPK, PI3K, and WNT signaling pathways underpins much of development and is deregulatedin cancer. In principle, combinatorial posttranslational modification of key lineage specific transcription factors would be an effective mean stointegrate critical signaling events. Understanding how this might be achieved is central to deciphering the impact of microenvironmental cues in development and disease. The microphthalmia-associated transcription factor MITF plays a crucial role in the development of melanocytes, the retinal pigment epithelium, osteoclasts, and mast cells and acts as a lineage survival oncogene in melanoma. MITF coordinates survival, differentiation, cell-cycle progression, cell migration, metabolism, and lysosome biogenesis. However, how the activity of this key transcriptionfactoriscontrolledremainspoorlyunderstood.Here,we showthatGSK3,downstreamfromboththePI3KandWntpathways, and BRAF/MAPK signaling converge to control MITF nuclear export. Phosphorylation of the melanocyte MITF-M isoform in response to BRAF/MAPK signaling primes for phosphorylation by GSK3, a kinase inhibited by both PI3K and Wnt signaling. Dual phosphorylation, but not monophosphorylation, then promotes MITF nuclear export by activatinga previously unrecognizedhydrophobic exportsignal. NonmelanocyteMITFisoformsexhibitpoorregulationbyMAPKsignaling, but instead their export is controlled by mTOR. We uncover here an unanticipated mode of MITF regulation that integrates the output of key developmental and cancer-associated signaling pathways to gate MITF flux through the import–export cycle. The results have significant implications for our understanding of melanoma progression and stem cell renewal.
2019-11-12 | PXD010782 | Pride
Project description:Cyclin-dependent kinases 4 and 6 (CDK4/6) are essential drivers of the cell cycle and are also critical for the initiation and progression of diverse malignancies. Pharmacological inhibitors targeting CDK4/6 have demonstrated significant activity against various tumor types such as breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i) (such as palbociclib) remains an immense obstacle in clinical and the underlying mechanisms have not been fully understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we report that the Microphthalmia-associated transcription factor (MITF), was significantly elevated in palbociclib-resistance cells. Inhibition of MITF can enhance the therapeutic efficacy of Palbociclib and surmount Palbociclib resistance both in vitro and in vivo. Then we found that MITF is interacting with OGT in Palbociclib-resistance cells, and we also identified that Ser49 is the main O-GlcNAc site of MITF. O-GlcNAc of MITF is critical to mediated Palbociclib-resistance in cells.
2024-05-30 | PXD042763 | Pride
Project description:The close integration of the MAPK, PI3K and WNT signaling pathways underpins much of development and is deregulated in cancer. In principle, combinatorial post-translational modification of key lineage–specific transcription factors would be an effective means to integrate critical signaling events. Understanding how this might be achieved is central to deciphering the impact of microenvironmental cues in development and disease. The microphthalmia associated transcription factor, MITF, plays a crucial role in the development of melanocytes, the retinal pigment epithelium, osteoclasts and mast cells, and acts as a lineage survival oncogene in melanoma. MITF coordinates survival, differentiation, cell cycle progression, cell migration, metabolism and lysosome biogenesis. Yet how the activity of this key transcription factor is controlled remains poorly understood. Here we show that GSK3b, downstream from both the PI3K and Wnt pathways, and BRAF/MAPK signaling converge to control MITF nuclear export. Phosphorylation of the melanocyte MITF-M isoform in response to BRAF/MAPK signaling primes for phosphorylation by GSK3b, a kinase inhibited by both PI3K and Wnt signaling. Dual phosphorylation, but not monophosphorylation, then promotes MITF nuclear export by activating a previously unrecognized hydrophobic export signal. Nonmelanocyte MITF isoforms exhibit poor regulation by MAPK signaling, but instead their export is controlled by mTOR. We uncover here an unanticipated mode of MITF regulation that integrates the output of key developmental and cancer-associated signaling pathways to gate MITF flux through the import-export cycle. The results have significant implications for our understanding of melanoma progression and stem cell renewal
2022-02-28 | PXD010665 | Pride