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Hierarchical regulation in a KRAS pathway-dependent transcriptional network revealed by a reverse-engineering approach (7TF and control)

ABSTRACT: RAS mutations are highly relevant for progression and therapy response of human tumours, but the genetic network that ultimately executes the oncogenic effects is poorly understood. Here we used a reverse-engineering approach in an ovarian cancer model to reconstruct KRAS oncogene-dependent cytoplasmic and transcriptional networks from perturbation experiments based on gene silencing and pathway inhibitor treatments. We measured mRNA and protein levels in manipulated cells by microarray, RT-PCR and Western Blot analysis, respectively. The reconstructed model revealed complex interactions among the transcriptional and cytoplasmic components, some of which were confirmed by double pertubation experiments. Interestingly, the transcription factors decomposed into two hierarchically arranged groups. To validate the model predictions we analysed growth parameters and transcriptional deregulation in the KRAS-transformed epithelial cells. As predicted by the model, we found two functional groups among the selected transcription factors. The experiments thus confirmed the predicted hierarchical transcription factor regulation and showed that the hierarchy manifests itself in downstream gene expression patterns and phenotype.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE38584 | GEO | 2012/08/01

SECONDARY ACCESSION(S): PRJNA168232

REPOSITORIES: GEO

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Hierarchical regulation in a KRAS pathway-dependent transcriptional network revealed by a reverse-engineering approach (RAS-ROSE and ROSE with siRNA)

Project description:RAS mutations are highly relevant for progression and therapy response of human tumours, but the genetic network that ultimately executes the oncogenic effects is poorly understood. Here we used a reverse-engineering approach in an ovarian cancer model to reconstruct KRAS oncogene-dependent cytoplasmic and transcriptional networks from perturbation experiments based on gene silencing and pathway inhibitor treatments. We measured mRNA and protein levels in manipulated cells by microarray, RT-PCR and Western Blot analysis, respectively. The reconstructed model revealed complex interactions among the transcriptional and cytoplasmic components, some of which were confirmed by double pertubation experiments. Interestingly, the transcription factors decomposed into two hierarchically arranged groups. To validate the model predictions we analysed growth parameters and transcriptional deregulation in the KRAS-transformed epithelial cells. As predicted by the model, we found two functional groups among the selected transcription factors. The experiments thus confirmed the predicted hierarchical transcription factor regulation and showed that the hierarchy manifests itself in downstream gene expression patterns and phenotype. RAS-ROSE cells and ROSE cells treated with Scrambled siRNA

2012-07-31 | E-GEOD-38585 | biostudies-arrayexpress

Hierarchical regulation in a KRAS pathway-dependent transcriptional network revealed by a reverse-engineering approach (7TF and control)

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2012-08-01 | GSE38585 | GEO

Hierarchical regulation in a KRAS-dependent transcriptional network revealed by a reverse-engineering approach

Project description:Mutations in RAS proteins occur in 30% of human tumours and have a high relevance in tumor progression. Despite the importance of the underlying genetic network that governs the effects of oncogenic RAS, it is still poorly understood. We developed and applied a reverse-engineering approach in order to reconstruct the network structure of the signaling and gene-regulatory network downstream of RAS from perturbation experiments. We performed microarray, RT-PCR and Western Blot analysis to detect mRNA and protein levels of cytoplasmatic and nuclear targets downstream of RAS after systematic perturbation of the signaling pathways and knock-down of selected transcription factors in KRAS-transformed ovarian surface epithelium cell lines. The reconstructed model shows that the investigated components are connected through a complex network. The transcription factors decomposed into two hierarchically arranged groups. While knock-down of all investigated transcription factors showed a partial reversion of the malignant phenotype, different growth assays show that these two groups of transcription factors control different functions in the malignant anchorage-independent growth and cell cycle regulation of the ROSE cells. Furthermore, the model showed strong regulatory interplay of inhibitory and activating interactions between the RAS-dependent trancriptional network and cytoplasmatic signaling components.

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