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

Jacqueline Salotti, Krisada Sakchaisri, Warren G. Tourtellotte, Peter F. Johnson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Oncogene-induced senescence (OIS) protects normal cells from transformation by Ras, 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-RasV12 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 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 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 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.

Original languageEnglish (US)
Pages (from-to)866-883
Number of pages18
JournalMolecular and cellular biology
Volume35
Issue number5
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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