Oncogenic KRAS recruits an expansive transcriptional network through mutant p53
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA664380 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12671500_1.fastq.gz | Fastqsanger.gz | |||
| SRR12671500_2.fastq.gz | Fastqsanger.gz | |||
| SRR12671501_1.fastq.gz | Fastqsanger.gz | |||
| SRR12671501_2.fastq.gz | Fastqsanger.gz | |||
| SRR12671502_1.fastq.gz | Fastqsanger.gz |
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Project description:The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF- B anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. This SuperSeries is composed of the following subset Series:; GSE17643: Profiling of immortalized human lung epithelial cells following oncogenic KRAS expression and TBK1 suppression; GSE17671: Profiling of immortalized human lung epithelial cells following infection with oncogenic KRAS (G12V) Experiment Overall Design: Refer to individual Series
2009-10-31 | E-GEOD-17672 | biostudies-arrayexpress
Project description:In this experiment the RNA of s.c. grown tumors of cancer cell lines of murine Ptf1aCre;Kras,Brg1-/- vs. Ptf1a;Kras;p53+/- PDA was isolated and analyzed for gene expression. Ptf1aCre;Kras,Brg1-/- s.c. PDA grows more benign as compared to Ptf1a;Kras;p53+/- PDA; and the rationale of this study was to identify genes responsible for this different biological behavior. Total RNA of s.c. tumors of Ptf1aCre;Kras,Brg1-/- vs. Ptf1a;Kras;p53+/- cancer cell lines was isolated, purified and analyzed on the deep sequencing platform.
2013-11-14 | E-GEOD-52332 | biostudies-arrayexpress
Project description:In several cancer types, STAT (Signal transducer and activator of transcription) transcription factors are constitutively activated. We previously identified a target gene, LPP/miR-28 (LIM domain containing preferred translocation partner in lipoma), induced by constitutive activation of STAT5, but not by transient cytokine-activated STAT5. Here, we demonstrate in transformed hematopoietic cells that binding of both STAT5B and p53 to chromatin is required for transcriptional activity of an alternative LPP/miR-28 promoter. Using a genome-wide approach, we identified 463 genomic positions at promoter regions where STAT5B and p53 are co-localized on the chromatin. At these positions, p53 chromatin binding is dependent on persistent STAT5B activation. The transcriptional activity of selected promoters bound by STAT5B and p53 was significantly changed upon STAT5 or p53 inhibition, and the transcription of these target genes is frequently altered in platelets of myeloproliferative neoplasm patients harboring mutations constitutively activating STAT5. These data suggest that the constitutive STAT5 activation recruits p53 in cancer cells and thereby activates oncogenic transcriptional programs. STAT5B and p53 ChIP-chip with or without JAK2 inhibition (ruxolitinib) to inhibit STAT5 phosphorylation and DNA binding.
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Project description:Oncogenic mutations in tumor cells regulate signaling both within tumor cells and heterotypic stromal cells. However, whether oncogenes regulate tumor cell signaling via stromal cells is poorly understood. Here we show that oncogenic KRAS (KRAS-G12D) uniquely regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with phosphoproteomic multiplexing we conducted a multivariate analysis of heterocellular KRAS-G12D signaling in Pancreatic Ductal Adenocarcinoma (PDA) cells. By engaging heterotypic fibroblasts, KRAS-G12D drives unique reciprocal signaling in tumor cells to employ additional kinases and double the number of regulated signaling nodes from cell-autonomous KRAS-G12D. Heterocellular signaling produces a distinct tumor cell phosphoproteome, total proteome, and increase mitochondria capacity via an IGF1R/AXL-AKT axis. Reciprocal KRAS-G12D phenotypes require a heterocellular context and are unreachable by cell-autonomous KRAS-G12D alone. These results demonstrate oncogene signaling should be viewed as a heterocellular process and our existing homocellular perspective underrepresents the extent of oncogene signaling in cancer.
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Project description:Lo A, Holmes K, Mundt F, Moorthi S, Fung I, Fereshetian S, Watson J, Carr SA, Mertins P, Berger A. Aberrant activation of RAS oncogenes is a prevalent event in lung adenocarcinoma, with somatic mutation of KRAS occurring in ~30% of tumors. Recently, we identified somatic mutation of the RAS-family GTPase RIT1 in lung adenocarcinoma, but relatively little is known about the biological pathways regulated by RIT1 and how these relate to the oncogenic KRAS network. Here we present quantitative proteomic and transcriptomic profiles from KRAS-mutant and RIT1-mutant isogenic lung epithelial cells and globally characterize the signaling networks regulated by each oncogene. We find that both mutant KRAS and mutant RIT1 promote S6 kinase, AKT, and RAF/MEK signaling, and promote epithelial-to-mesenchymal transition and immune evasion via HLA protein loss. However, KRAS and RIT1 diverge in regulation of phosphoproteins including EGFR, USO1, and AHNAK proteins. The majority of the proteome changes are related to altered transcriptional regulation, but a small subset of proteins are differentially regulated at the post-transcriptional level, including intermediate filament proteins, metallothioneins, and MHC Class I proteins, which are profoundly suppressed by oncogenic KRAS and RIT1 variants. These data provide the first global, unbiased characterization of oncogenic RIT1 network and identify the shared and divergent functions of oncogenic RIT1 and KRAS GTPases in lung cancer.
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Project description:Aberrant activation of RAS oncogenes is a prevalent event in lung adenocarcinoma, with somatic mutation of KRAS occurring in ~30% of tumors. Recently, we identified somatic mutation of the RAS-family GTPase RIT1 in lung adenocarcinoma, but relatively little is known about the biological pathways regulated by RIT1 and how these relate to the oncogenic KRAS network. Here we present (quantitative proteomic and) transcriptomic profiles from KRAS-mutant and RIT1-mutant isogenic lung epithelial cells and globally characterize the signaling networks regulated by each oncogene.
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