title: An Arf-Egr-C/EBPβ pathway linked to ras-induced senescence and cancer.
abstract: Oncogene-induced senescence (OIS) protects normal cells from transformation by Ras, whereas cells lacking p14/p19(Arf) 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 p19(Arf) loss. Here, we report that members of the serum-induced early growth response (Egr) protein family are also downregulated in 3T3(Ras) 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 3T3(Ras) cells. Egr2 and Egr3 levels were also reduced in Ras(V12)-expressing p19(Arf) null mouse embryonic fibroblasts (MEFs), and overall Egr DNA-binding activity was suppressed in Arf-deficient 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.
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Salotti
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
authors.forename: Krisada
authors.initials: K
authors.lastname: Sakchaisri
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Warren G
authors.initials: WG
authors.lastname: Tourtellotte
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA johnsope@mail.nih.gov.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Johnson
mesh_terms: D016475:3T3 Cells; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D018631:ras Proteins