title: CCAAT/enhancer binding protein-beta is a mediator of keratinocyte survival and skin tumorigenesis involving oncogenic Ras signaling.
abstract: The basic leucine zipper transcription factor CCAAT/enhancer binding protein-beta (C/EBPbeta) is expressed in many cell types, including keratinocytes. C/EBPbeta activity can be increased by phosphorylation through pathways stimulated by oncogenic Ras, although the biological implications of Ras-C/EBPbeta signaling are not currently understood. We report here that C/EBPbeta-nullizygous mice are completely refractory to skin tumor development induced by a variety of carcinogens and carcinogenesis protocols, including 7,12-dimethylbenz[a]anthracene-initiation/12-O-tetradecanoylphorbol 13-acetate promotion, that produce tumors containing oncogenic Ras mutations. No significant differences in TPA-induced epidermal keratinocyte proliferation were observed in C/EBPbeta-null versus wild-type mice. However, apoptosis was significantly elevated (17-fold) in the epidermal keratinocytes of 7,12-dimethylbenz[a]anthracene-treated C/EBPbeta-null mice compared with wild-type mice. In v-Ha-ras transgenic mice, C/EBPbeta deficiency also led to greatly reduced skin tumor multiplicity and size, providing additional evidence for a tumorigenesis pathway linking Ras and C/EBPbeta. Oncogenic Ras potently stimulated C/EBPbeta to activate a C/EBP-responsive promoter-reporter in keratinocytes and mutating an ERK1/2 phosphorylation site (T188) in C/EBPbeta abolished this Ras effect. Finally, we observed that C/EBPbeta participates in oncogenic Ras-induced transformation of NIH 3T3 cells. These findings indicate that C/EBPbeta has a critical role in Ras-mediated tumorigenesis and cell survival and implicate C/EBPbeta as a target for tumor inhibition.
authors.affiliation: Cell Signaling and Cancer Group, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633, USA.
authors.forename: Songyun
authors.initials: S
authors.lastname: Zhu
authors.forename: Kyungsil
authors.initials: K
authors.lastname: Yoon
authors.forename: Esta
authors.initials: E
authors.lastname: Sterneck
authors.forename: Peter F
authors.initials: PF
authors.lastname: Johnson
authors.forename: Robert C
authors.initials: RC
authors.lastname: Smart
mesh_terms: D016475:3T3 Cells; D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D002273:Carcinogens; D002455:Cell Division; D002470:Cell Survival; D017930:Genes, Reporter; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009153:Mutagens; D009154:Mutation; D015689:Oncogene Protein p21(ras) / Q000235:genetics* / Q000502:physiology*; D010766:Phosphorylation; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors; D015533:Transcriptional Activation
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D002273:Carcinogens; D009153:Mutagens; D015127:9,10-Dimethyl-1,2-benzanthracene; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015689:Oncogene Protein p21(ras); D001973:Bromodeoxyuridine; D013755:Tetradecanoylphorbol Acetate