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: Songyun Zhu, Kyungsil Yoon, Esta Sterneck, Peter F Johnson, Robert C Smart
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 99 Issue 1 Pg. 207-12 (Jan 08 2002) ISSN: 0027-8424 [Print] United States
• PMID: 11756662 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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

Topics

• 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