An Arf-Egr-C/EBPβ Pathway Linked to Ras-Induced Senescence and Cancer

Oncogene-induced senescence (OIS) protects normal cells from transformation byRas , whereas cells lacking p14/p19Arf or other tumor suppressors can be transformed. The transcription factor C/EBPβ is required for OIS in primary fibroblasts but is downregulated by H-Ras V12 in immortalized NIH 3T3 cells through a mechanism involving p19Arf loss. Here, we report that members of the serum-induced early growth response (Egr) protein family are also downregulated in 3T3Ras cells and directly and redundantly controlCebpb gene transcription. Egr1, Egr2, and Egr3 recognize three sites in theCebpb promoter and associate transiently with this region after serum stimulation, coincident withCebpb induction. Codepletion of all three Egrs preventedCebpb expression, and serum induction of Egrs was significantly blunted in 3T3Ras cells. Egr2 and Egr3 levels were also reduced in RasV12 -expressing p19Arf null mouse embryonic fibroblasts (MEFs), and overall Egr DNA-binding activity was suppressed in Arf-deficient but not wild-type (WT) MEFs, leading toCebpb downregulation. Analysis of human cancers revealed a strong correlation betweenEGR levels andCEBPB expression, regardless of whetherCEBPB was increased or decreased in tumors. Moreover, overexpression of Egrs in tumor cell lines inducedCEBPB 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.