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PMID: 11756662 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

CCAAT/enhancer binding protein-beta is a mediator of keratinocyte survival and skin tumorigenesis involving oncogenic Ras signaling.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 1 ·2002-01-08 ·Pages 207-12

Zhu S, Yoon K, Sterneck E, Johnson PF, Smart RC

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.

MeSH Terms
3T3 Cells 9,10-Dimethyl-1,2-benzanthracene Animals Apoptosis Blotting, Western Bromodeoxyuridine/pharmacology CCAAT-Enhancer-Binding Protein-beta/genetics,metabolism,physiology Carcinogens Cell Division Cell Survival Genes, Reporter Keratinocytes/cytology,metabolism Mice Mice, Inbred BALB C Mice, Transgenic Mitogen-Activated Protein Kinase 1/metabolism Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases/metabolism Mutagens Mutation Oncogene Protein p21(ras)/genetics,physiology Phosphorylation Signal Transduction Skin Neoplasms/metabolism Tetradecanoylphorbol Acetate Time Factors Transcriptional Activation
Chemicals
CCAAT-Enhancer-Binding Protein-beta Carcinogens Mutagens 9,10-Dimethyl-1,2-benzanthracene Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases Oncogene Protein p21(ras) Bromodeoxyuridine Tetradecanoylphorbol Acetate
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Zhu Songyun
Cell Signaling and Cancer Group, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633, USA.
Yoon Kyungsil
Sterneck Esta
Johnson Peter F
Smart Robert C
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.012437299
Published
2002-01-08
Epub
2001-00-26
Pages
207-12
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC117540
Subset
IM
Grants
NCI NIH HHS · R01 CA046637 · United States
NCI NIH HHS · CA46637 · United States
External Links
PubMed source DOI: 10.1073/pnas.012437299 PMC Full Text View journal details
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