The Experts below are selected from a list of 161187 Experts worldwide ranked by ideXlab platform
Jingwei Cheng - One of the best experts on this subject based on the ideXlab platform.
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merkel cell polyomavirus recruits Mycl to the ep400 complex to promote oncogenesis
PLOS Pathogens, 2017Co-Authors: Christian Berrios, Donglim Esther Park, Jingwei Cheng, Elizabeth A White, Reety Arora, Rosa Yoon, Timothy Branigan, Tengfei Xiao, Thomas WesterlingAbstract:Merkel cell carcinoma (MCC) frequently contains integrated copies of Merkel cell polyomavirus DNA that express a truncated form of Large T antigen (LT) and an intact Small T antigen (ST). While LT binds RB and inactivates its tumor suppressor function, it is less clear how ST contributes to MCC tumorigenesis. Here we show that ST binds specifically to the Myc homolog MycL (L-Myc) and recruits it to the 15-component EP400 histone acetyltransferase and chromatin remodeling complex. We performed a large-scale immunoprecipitation for ST and identified co-precipitating proteins by mass spectrometry. In addition to protein phosphatase 2A (PP2A) subunits, we identified MycL and its heterodimeric partner MAX plus the EP400 complex. Immunoprecipitation for MAX and EP400 complex components confirmed their association with ST. We determined that the ST-MycL-EP400 complex binds together to specific gene promoters and activates their expression by integrating chromatin immunoprecipitation with sequencing (ChIP-seq) and RNA-seq. MycL and EP400 were required for maintenance of cell viability and cooperated with ST to promote gene expression in MCC cell lines. A genome-wide CRISPR-Cas9 screen confirmed the requirement for MycL and EP400 in MCPyV-positive MCC cell lines. We demonstrate that ST can activate gene expression in a EP400 and MycL dependent manner and this activity contributes to cellular transformation and generation of induced pluripotent stem cells.
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merkel cell polyomavirus small t antigen promotes pro glycolytic metabolic perturbations required for transformation
PLOS Pathogens, 2016Co-Authors: Christian Berrios, Megha Padi, Mark A Keibler, Donglim Esther Park, Vadim Molla, Jingwei Cheng, Gregory Stephanopoulos, John Quackenbush, James A DecaprioAbstract:Merkel cell polyomavirus (MCPyV) is an etiological agent of Merkel cell carcinoma (MCC), a highly aggressive skin cancer. The MCPyV small tumor antigen (ST) is required for maintenance of MCC and can transform normal cells. To gain insight into cellular perturbations induced by MCPyV ST, we performed transcriptome analysis of normal human fibroblasts with inducible expression of ST. MCPyV ST dynamically alters the cellular transcriptome with increased levels of glycolytic genes, including the monocarboxylate lactate transporter SLC16A1 (MCT1). Extracellular flux analysis revealed increased lactate export reflecting elevated aerobic glycolysis in ST expressing cells. Inhibition of MCT1 activity suppressed the growth of MCC cell lines and impaired MCPyV-dependent transformation of IMR90 cells. Both NF-κB and Myc have been shown to regulate MCT1 expression. While Myc was required for MCT1 induction, MCPyV-induced MCT1 levels decreased following knockdown of the NF-κB subunit RelA, supporting a synergistic activity between MCPyV and Myc in regulating MCT1 levels. Several MCC lines had high levels of MycL and MycN but not Myc. Increased levels of MycL was more effective than Myc or MycN in increasing extracellular acidification in MCC cells. Our results demonstrate the effects of MCPyV ST on the cellular transcriptome and reveal that transformation is dependent, at least in part, on elevated aerobic glycolysis.
Bruce A Edgar - One of the best experts on this subject based on the ideXlab platform.
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Myc dependent regulation of ribosomal rna synthesis during drosophila development
Nature Cell Biology, 2005Co-Authors: Savraj S Grewal, Ling Li, Amir Orian, Robert N Eisenman, Bruce A EdgarAbstract:Regulating ribosome number is thought to control cellular growth1. Synthesis of ribosomal RNA (rRNA) is a limiting step in ribosome biogenesis and rates of rRNA synthesis are generally altered depending on the growth status of a cell2,3. Although studies in unicellular systems have addressed the mechanisms by which this occurs4,5, few studies have applied a genetic approach to examine growth-dependent control of rRNA synthesis in metazoans. Here, we show that in Drosophila melanogaster Myc (dMyc) is a regulator of rRNA synthesis. Expression of dMyc is both necessary and sufficient to control rRNA synthesis and ribosome biogenesis during larval development. Stimulation of rRNA synthesis by dMyc is mediated through a rapid, coordinated increase in the levels of the Pol I transcriptional machinery. In addition, the growth effects of dMyc in larval wing imaginal discs require de novo rRNA synthesis. We suggest that during animal development, the control of rRNA synthesis and ribosome biogenesis is an essential Myc function.
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drosophila Myc regulates cellular growth during development
Cell, 1999Co-Authors: Laura A Johnston, Robert N Eisenman, Bruce A Edgar, David A Prober, Peter GallantAbstract:Transcription factors of the Myc proto-oncogene family promote cell division, but how they do this is poorly understood. Here we address the functions of Drosophila Myc (dMyc) during development. Using mosaic analysis in the fly wing, we show that loss of dMyc retards cellular growth (accumulation of cell mass) and reduces cell size, whereas dMyc overproduction increases growth rates and cell size. dMyc-induced growth promotes G1/S progression but fails to accelerate cell division because G2/M progression is independently controlled by Cdc25/String. We also show that the secreted signal Wingless patterns growth in the wing primordium by modulating dMyc expression. Our results indicate that dMyc links patterning signals to cell division by regulating primary targets involved in cellular growth and metabolism.
Savraj S Grewal - One of the best experts on this subject based on the ideXlab platform.
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Myc dependent regulation of ribosomal rna synthesis during drosophila development
Nature Cell Biology, 2005Co-Authors: Savraj S Grewal, Ling Li, Amir Orian, Robert N Eisenman, Bruce A EdgarAbstract:Regulating ribosome number is thought to control cellular growth1. Synthesis of ribosomal RNA (rRNA) is a limiting step in ribosome biogenesis and rates of rRNA synthesis are generally altered depending on the growth status of a cell2,3. Although studies in unicellular systems have addressed the mechanisms by which this occurs4,5, few studies have applied a genetic approach to examine growth-dependent control of rRNA synthesis in metazoans. Here, we show that in Drosophila melanogaster Myc (dMyc) is a regulator of rRNA synthesis. Expression of dMyc is both necessary and sufficient to control rRNA synthesis and ribosome biogenesis during larval development. Stimulation of rRNA synthesis by dMyc is mediated through a rapid, coordinated increase in the levels of the Pol I transcriptional machinery. In addition, the growth effects of dMyc in larval wing imaginal discs require de novo rRNA synthesis. We suggest that during animal development, the control of rRNA synthesis and ribosome biogenesis is an essential Myc function.
Amir Orian - One of the best experts on this subject based on the ideXlab platform.
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A Myc–Groucho complex integrates EGF and Notch signaling to regulate neural development
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Amir Orian, Jeffrey J Delrow, Alicia E. Rosales Nieves, David Metzger, Ze'ev Paroush, Mona Abed, Robert N Eisenman, Susan M. ParkhurstAbstract:Integration of patterning cues via transcriptional networks to coordinate gene expression is critical during morphogenesis and misregulated in cancer. Using DNA adenine methyltransferase (Dam)ID chromatin profiling, we identified a protein–protein interaction between the Drosophila Myc oncogene and the Groucho corepressor that regulates a subset of direct dMyc targets. Most of these shared targets affect fate or mitosis particularly during neurogenesis, suggesting the dMyc–Groucho complex may coordinate fate acquisition with mitotic capacity during development. We find an antagonistic relationship between dMyc and Groucho that mimics the antagonistic interactions found for EGF and Notch signaling: dMyc is required to specify neuronal fate and enhance neuroblast mitosis, whereas Groucho is required to maintain epithelial fate and inhibit mitosis. Our results suggest that the dMyc–Groucho complex defines a previously undescribed mechanism of Myc function and may serve as the transcriptional unit that integrates EGF and Notch inputs to regulate early neuronal development.
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Myc dependent regulation of ribosomal rna synthesis during drosophila development
Nature Cell Biology, 2005Co-Authors: Savraj S Grewal, Ling Li, Amir Orian, Robert N Eisenman, Bruce A EdgarAbstract:Regulating ribosome number is thought to control cellular growth1. Synthesis of ribosomal RNA (rRNA) is a limiting step in ribosome biogenesis and rates of rRNA synthesis are generally altered depending on the growth status of a cell2,3. Although studies in unicellular systems have addressed the mechanisms by which this occurs4,5, few studies have applied a genetic approach to examine growth-dependent control of rRNA synthesis in metazoans. Here, we show that in Drosophila melanogaster Myc (dMyc) is a regulator of rRNA synthesis. Expression of dMyc is both necessary and sufficient to control rRNA synthesis and ribosome biogenesis during larval development. Stimulation of rRNA synthesis by dMyc is mediated through a rapid, coordinated increase in the levels of the Pol I transcriptional machinery. In addition, the growth effects of dMyc in larval wing imaginal discs require de novo rRNA synthesis. We suggest that during animal development, the control of rRNA synthesis and ribosome biogenesis is an essential Myc function.
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genomic binding by the drosophila Myc max mad mnt transcription factor network
Genes & Development, 2003Co-Authors: Amir Orian, Jeffrey J Delrow, Bas Van Steensel, Harmen J Bussemaker, Tomoyuki Sawado, Eleanor M Williams, Lenora W M Loo, Shaun M Cowley, Cynthia Yost, Sarah B PierceAbstract:The Myc/Max/Mad transcription factor network is critically involved in cell behavior; however, there is relatively little information on its genomic binding sites. We have employed the DamID method to carry out global genomic mapping of the Drosophila Myc, Max, and Mad/Mnt proteins. Each protein was tethered to Escherichia coli DNA adenine-methyltransferase (Dam) permitting methylation proximal to in vivo binding sites in Kc cells. Microarray analyses of methylated DNA fragments reveals binding to multiple loci on all major Drosophila chromosomes. This approach also reveals dynamic interactions among network members as we find that increased levels of dMax influence the extent of dMyc, but not dMnt, binding. Computer analysis using the REDUCE algorithm demonstrates that binding regions correlate with the presence of E-boxes, CG repeats, and other sequence motifs. The surprisingly large number of directly bound loci (� 15% of coding regions) suggests that the network interacts widely with the genome. Furthermore, we employ microarray expression analysis to demonstrate that hundreds of DamID-binding loci correspond to genes whose expression is directly regulated by dMyc in larvae. These results suggest that a fundamental aspect of Max network function involves widespread binding and regulation of gene expression.
Christian Berrios - One of the best experts on this subject based on the ideXlab platform.
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merkel cell polyomavirus recruits Mycl to the ep400 complex to promote oncogenesis
PLOS Pathogens, 2017Co-Authors: Christian Berrios, Donglim Esther Park, Jingwei Cheng, Elizabeth A White, Reety Arora, Rosa Yoon, Timothy Branigan, Tengfei Xiao, Thomas WesterlingAbstract:Merkel cell carcinoma (MCC) frequently contains integrated copies of Merkel cell polyomavirus DNA that express a truncated form of Large T antigen (LT) and an intact Small T antigen (ST). While LT binds RB and inactivates its tumor suppressor function, it is less clear how ST contributes to MCC tumorigenesis. Here we show that ST binds specifically to the Myc homolog MycL (L-Myc) and recruits it to the 15-component EP400 histone acetyltransferase and chromatin remodeling complex. We performed a large-scale immunoprecipitation for ST and identified co-precipitating proteins by mass spectrometry. In addition to protein phosphatase 2A (PP2A) subunits, we identified MycL and its heterodimeric partner MAX plus the EP400 complex. Immunoprecipitation for MAX and EP400 complex components confirmed their association with ST. We determined that the ST-MycL-EP400 complex binds together to specific gene promoters and activates their expression by integrating chromatin immunoprecipitation with sequencing (ChIP-seq) and RNA-seq. MycL and EP400 were required for maintenance of cell viability and cooperated with ST to promote gene expression in MCC cell lines. A genome-wide CRISPR-Cas9 screen confirmed the requirement for MycL and EP400 in MCPyV-positive MCC cell lines. We demonstrate that ST can activate gene expression in a EP400 and MycL dependent manner and this activity contributes to cellular transformation and generation of induced pluripotent stem cells.
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merkel cell polyomavirus small t antigen promotes pro glycolytic metabolic perturbations required for transformation
PLOS Pathogens, 2016Co-Authors: Christian Berrios, Megha Padi, Mark A Keibler, Donglim Esther Park, Vadim Molla, Jingwei Cheng, Gregory Stephanopoulos, John Quackenbush, James A DecaprioAbstract:Merkel cell polyomavirus (MCPyV) is an etiological agent of Merkel cell carcinoma (MCC), a highly aggressive skin cancer. The MCPyV small tumor antigen (ST) is required for maintenance of MCC and can transform normal cells. To gain insight into cellular perturbations induced by MCPyV ST, we performed transcriptome analysis of normal human fibroblasts with inducible expression of ST. MCPyV ST dynamically alters the cellular transcriptome with increased levels of glycolytic genes, including the monocarboxylate lactate transporter SLC16A1 (MCT1). Extracellular flux analysis revealed increased lactate export reflecting elevated aerobic glycolysis in ST expressing cells. Inhibition of MCT1 activity suppressed the growth of MCC cell lines and impaired MCPyV-dependent transformation of IMR90 cells. Both NF-κB and Myc have been shown to regulate MCT1 expression. While Myc was required for MCT1 induction, MCPyV-induced MCT1 levels decreased following knockdown of the NF-κB subunit RelA, supporting a synergistic activity between MCPyV and Myc in regulating MCT1 levels. Several MCC lines had high levels of MycL and MycN but not Myc. Increased levels of MycL was more effective than Myc or MycN in increasing extracellular acidification in MCC cells. Our results demonstrate the effects of MCPyV ST on the cellular transcriptome and reveal that transformation is dependent, at least in part, on elevated aerobic glycolysis.
