An Arf-Egr-C/EBPβ pathway linked to ras-induced senescence and cancer

Abstract

© 2015, American Society for Microbiology. Oncogene-induced senescence (OIS) protects normal cells from transformation by Ras, whereas cells lacking p14/p19Arfor other tumor suppressors can be transformed. The transcription factor C/EBPβ is required for OIS in primary fibroblasts but is downregulated by H-RasV12in immortalized NIH 3T3 cells through a mechanism involving p19Arfloss. Here, we report that members of the serum-induced early growth response (Egr) protein family are also downregulated in 3T3Rascells and directly and redundantly control Cebpb gene transcription. Egr1, Egr2, and Egr3 recognize three sites in the Cebpb promoter and associate transiently with this region after serum stimulation, coincident with Cebpb induction. Codepletion of all three Egrs prevented Cebpb expression, and serum induction of Egrs was significantly blunted in 3T3Rascells. Egr2 and Egr3 levels were also reduced in RasV12-expressing p19Arfnull mouse embryonic fibroblasts (MEFs), and overall Egr DNA-binding activity was suppressed in Arfdeficient but not wild-type (WT) MEFs, leading to Cebpb downregulation. Analysis of human cancers revealed a strong correlation between EGR levels and CEBPB expression, regardless of whether CEBPB was increased or decreased in tumors. Moreover, overexpression of Egrs in tumor cell lines induced CEBPB and inhibited proliferation. Thus, our findings identify the Arf-Egr-C/ EBPβ axis as an important determinant of cellular responses (senescence or transformation) to oncogenic Ras signaling.