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

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE24668 | GEO | 2011/03/01

SECONDARY ACCESSION(S): PRJNA132543

REPOSITORIES: GEO