MYC protein interactome profiling reveals functionally distinct regions that cooperate to drive tumorigenesis (ChIP-Seq)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA481997 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7543210.fastq.gz | Fastqsanger.gz | |||
| SRR7543209.fastq.gz | Fastqsanger.gz |
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Project description:MYC protein interactome profiling reveals functionally distinct regions that cooperate to drive tumorigenesis
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2018-11-08 | GSE117408 | GEO
Project description:MYC is a potent oncogene associated with aggressive disease in many distinct tumor types. Transforming members of the MYC family (MYC, MYCL1, MYCN) encode transcription factors containing six highly conserved regions, termed MYC homology Boxes (MBs). Here, we conduct proteomic profiling of the MB interactomes, demonstrating that half of MYC interactors require one or more MBs for binding. Comprehensive phenotypic analyses revealed that two MBs are universally required for transformation. MBII interaction with acetyltransferase-containing complexes results in histone hyperacetylation and is essential for MYC-dependent tumor initiation. By contrast, MB0 interacts with transcription elongation factors through direct binding to the general transcription factor TFIIF, and deletion of MB0 severely inhibits tumor growth but is dispensable for tumor initiation. Notably, the full transforming activity of MYC can be restored upon co-expression of MB0 and MBII deletion mutants, indicating that these two regions confer unique biological functions, each required for oncogenic MYC activity.
2018-11-08 | GSE117407 | GEO
Project description:MYC is a potent oncogene associated with aggressive disease in many distinct tumor types. Transforming members of the MYC family (MYC, MYCL1, MYCN) encode transcription factors containing six highly conserved regions, termed MYC homology Boxes (MBs). Here, we conduct proteomic profiling of the MB interactomes, demonstrating that half of MYC interactors require one or more MBs for binding. Comprehensive phenotypic analyses revealed that two MBs are universally required for transformation. MBII interaction with acetyltransferase-containing complexes results in histone hyperacetylation and is essential for MYC-dependent tumor initiation. By contrast, MB0 interacts with transcription elongation factors through direct binding to the general transcription factor TFIIF, and deletion of MB0 severely inhibits tumor growth but is dispensable for tumor initiation. Notably, the full transforming activity of MYC can be restored upon co-expression of MB0 and MBII deletion mutants, indicating that these two regions confer unique biological functions, each required for oncogenic MYC activity.
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Project description:The fibroblast growth factor pathway is known to cooperate with the highly oncogenic Wnt/ï¢-catenin pathway in mouse models of breast cancer. To investigate the mechanisms involved in this cooperativity, we utilized MMTV-driven transgenic mouse lines expressing a drug-inducible model for FGF Receptor signaling (iFGFR) crossed with the previously characterized MMTV-Wnt-1 mouse model. In these bigenic mice, both iFGFR1 and iFGFR2 activation resulted in a dramatic enhancement of mammary tumorigenesis. Tumor microarray analysis identified no transcriptional enhancement of Wnt/ï¢-catenin targets, however, identified a protein translational gene signature that also correlated with elevated FGFR1 and FGFR2 expression in several human breast cancer data sets. Additionally, iFGFR1 activation resulted in enhanced polysome recruitment and a marked increase in protein expression of several different Wnt/ï¢-catenin target oncogenes. Rapid FGFR-induced ERK activation and phosphorylation of key translation regulators was observed both in vivo in the transgenic mouse model, and in human breast cancer cell lines treated with exogenous FGF. These studies suggest that translational regulation is a key rate-limiting step required for oncogenic cooperativity between the Wnt and FGF pathways. reference X sample
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Project description:EIF1AX-A113 splice and RAS mutations cooperate to drive thyroid tumorigenesis through ATF4 and c-MYC
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Project description:Translation initiation in higher eukaryotes is orchestrated by the tight regulation of the cap binding and the 43S pre-initiation complexes (PIC). The PIC component eukaryotic initiation factor 1A (EIF1A), encoded on human chromosomes X and Y by EIF1AX and EIF1AY, respectively, is essential for recruitment of the ternary complex and for assembling the 43S PIC, which after recruitment onto capped mRNAs scans their 5’UTR and localizes the AUG to initiate translation. Recurrent EIF1AX mutations are found in several cancers, including ~1% of papillary thyroid cancers in a mutually exclusive manner with other drivers (BRAF, RAS, and oncogenic fusions). They are enriched in advanced thyroid cancers (11%) where they display a striking co-occurrence with RAS, which we show cooperate to induce tumorigenesis in mouse models and in isogenic cell lines. The C-terminal tail EIF1AX-A113splice mutation is the most prevalent in advanced thyroid cancer, and private to this disease. We found that EIF1AX-A113spl variants stabilize the PIC and induces ATF4 expression, a sensor of cellular stress, which is co-opted to suppress EIF-2α phosphorylation, thus enabling a general increase in protein synthetic rate. RAS stabilizes c-MYC, an effect augmented by EIF1AX-A113spl. ATF4 and c-MYC induce expression of aminoacid transporters, and enhance sensitivity of mTOR to aminoacid supply. These mutually reinforcing events generate therapeutic vulnerabilities to MEK, BRD4 and mTOR kinase inhibitors. The RNA-Seq and Ribosome Profiling samples provided here were used to support the claim of increased translational efficiency of ATF4.
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Project description:The fibroblast growth factor pathway is known to cooperate with the highly oncogenic Wnt/beta-catenin pathway in mouse models of breast cancer. To investigate the mechanisms involved in this cooperativity, we utilized MMTV-driven transgenic mouse lines expressing a drug-inducible model for FGF Receptor signaling (iFGFR) crossed with the previously characterized MMTV-Wnt-1 mouse model. In these bigenic mice, both iFGFR1 and iFGFR2 activation resulted in a dramatic enhancement of mammary tumorigenesis. Tumor microarray analysis identified no transcriptional enhancement of Wnt/beta-catenin targets, however, identified a protein translational gene signature that also correlated with elevated FGFR1 and FGFR2 expression in several human breast cancer data sets. Additionally, iFGFR1 activation resulted in enhanced polysome recruitment and a marked increase in protein expression of several different Wnt/beta-catenin target oncogenes. Rapid FGFR-induced ERK activation and phosphorylation of key translation regulators was observed both in vivo in the transgenic mouse model, and in human breast cancer cell lines treated with exogenous FGF. These studies suggest that translational regulation is a key rate-limiting step required for oncogenic cooperativity between the Wnt and FGF pathways.
2010-03-01 | GSE17916 | GEO
Project description:H. pylori infection is the strongest known risk factor for gastric carcinoma. The activation of the yes-associated protein 1 (YAP) and β-catenin pathways has been associated with multiple tumor types. In this study, we investigated the crosstalk between the YAP and β-catenin pathways in H. pylori-associated gastric tumorigenesis. Immunohistochemical analysis of YAP and β-catenin expression was performed in human gastric cancer tissues. The small molecules Super-TDU and KYA1797K, pharmacological inhibitors of YAP and β-catenin, respectively, were used to investigate the role of these signaling pathways in H. pylori-induced gastric carcinogenesis in murine models of infection. The common downstream targets of YAP and β-catenin signaling were evaluated by RNA sequencing (RNA-seq). Western blot, immunofluorescence, luciferase, RT-PCR, immunoprecipitation, cell counting kit-8 (CCK8), EdU and spheroid assays were used. H. pylori infection promoted YAP and β-catenin nuclear accumulation and transcriptional activity in gastric epithelial cells and transgenic insulin-gastrin (INS-GAS) mice, whereas silencing of both YAP and β-catenin synergistically inhibited H. pylori-induced cell proliferation and expansion. In addition, YAP was found to directly interact with β-catenin and knockdown of YAP suppressed H. pylori-induced nuclear translocation of β-catenin. Moreover, downstream genes caudal-type homeobox 2 (CDX2), leucine-rich repeat containing G protein-coupled receptor 5 (LGR5) and RuvB like AAA ATPase 1 (RUVBL1) were shared by both YAP and β-catenin signaling. Furthermore, treatment with the YAP inhibitor Super-TDU or β-catenin inhibitor KYA1797A significantly alleviated gastric inflammation and epithelial DNA damage in H. pylori-infected mice. Finally, the elevation of gastric YAP was positively correlated with β-catenin expression in human gastric cancer tissues. These findings indicate that YAP and β-catenin synergistically promote H. pylori-induced gastric carcinogenesis via their physical interaction and reveal that CDX2, LGR5 and RUVBL1 are the downstream genes shared by both the YAP and β-catenin signaling pathways, and potentially contribute to H. pylori pathogenesis.
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