GenomeRNAi - a database for RNAi phenotypes and reagents
TitleScreen TitleAssayBiomodelSpecies
Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Wajapeyee et al. (2008) B-Raf senescence Genetic interaction with B-RafPFFs (human primary foreskin fibroblasts)H. sapiens

Abstract

Expression of an oncogene in a primary cell can, paradoxically, block proliferation by inducing senescence or apoptosis through pathways that remain to be elucidated. Here we perform genome-wide RNA-interference screening to identify 17 genes required for an activated BRAF oncogene (BRAFV600E) to block proliferation of human primary fibroblasts and melanocytes. Surprisingly, we find a secreted protein, IGFBP7, has a central role in BRAFV600E-mediated senescence and apoptosis. Expression of BRAFV600E in primary cells leads to synthesis and secretion of IGFBP7, which acts through autocrine/paracrine pathways to inhibit BRAF-MEK-ERK signaling and induce senescence and apoptosis. Apoptosis results from IGFBP7-mediated upregulation of BNIP3L, a proapoptotic BCL2 family protein. Recombinant IGFBP7 (rIGFBP7) induces apoptosis in BRAFV600E-positive human melanoma cell lines, and systemically administered rIGFBP7 markedly suppresses growth of BRAFV600E-positive tumors in xenografted mice. Immunohistochemical analysis of human skin, nevi, and melanoma samples implicates loss of IGFBP7 expression as a critical step in melanoma genesis.

Screen details


Stable Id: GR00094-A-0
Screen title: B-Raf senescence
Assay: Genetic interaction with B-Raf
Method: Sequencing
Scope:
Screen type: Cell-based
Species: Homo sapiens
Biosource: Cell line
Biomodel: PFFs (human primary foreskin fibroblasts)
Library: , shRNAmir library (release 1.20; Open Biosystems)
Reagent type: shRNA
Score type: np
Cutoff: np
Notes: