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PMID: 16205634 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Conditional ablation of C/EBP beta demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis.

Oncogene ·Vol. 25 ·No. 8 ·2006-02-23 ·Pages 1272-1276

Sterneck E, Zhu S, Ramirez A, Jorcano JL, Smart RC

Abstract

The CCAAT/enhancer binding protein beta (C/EBP beta) is implicated in the regulation of many different molecular and physiological processes. Mice with a germline deletion of C/EBP beta (C/EBP beta(-/-)) display phenotypes in a multitude of cell types and organ systems, including skin where C/EBP beta(-/-) mice exhibit increased apoptosis in epidermal keratinocytes in response to carcinogen treatment and are completely resistant to carcinogen-induced skin tumorigenesis. To determine the contribution of systemic versus cell autonomous functions of C/EBP beta to specific phenotypes, mice with a conditional 'floxed' C/EBP beta null allele were generated. Epidermal-specific deletion of C/EBP beta was achieved by Cre recombinase expression from a keratin 5 (K5) promoter. Similar to C/EBP beta(-/-) mice, K5-Cre;C/EBP beta(fl/fl) mice were completely refractory to 7,12 dimethylbenz[a]anthracene (DMBA)-induced skin tumorigenesis and these mice displayed increased DMBA-induced apoptosis in epidermal keratinocytes compared to wild-type mice. In contrast, mice lacking the related gene, C/EBP delta, were not resistant to DMBA-induced skin tumorigenesis, indicating a unique role of C/EBP beta in skin tumor development. Our findings demonstrate that C/EBP beta exerts an essential, keratinocyte-intrinsic role in cell survival in response to carcinogen treatment and the elimination of C/EBP beta in keratinocytes is sufficient to confer complete resistance of the skin to chemical carcinogenesis.

MeSH Terms
9,10-Dimethyl-1,2-benzanthracene/toxicity Animals Apoptosis CCAAT-Enhancer-Binding Protein-beta/genetics,physiology Carcinogens/toxicity Female Integrases/metabolism Keratin-15 Keratin-5 Keratinocytes/metabolism,pathology Keratins/genetics Mice Mice, Inbred C57BL Mice, Knockout Promoter Regions, Genetic Skin Neoplasms/chemically induced,metabolism,pathology Tetradecanoylphorbol Acetate/toxicity
Chemicals
CCAAT-Enhancer-Binding Protein-beta Carcinogens Keratin-15 Keratin-5 Krt15 protein, mouse 9,10-Dimethyl-1,2-benzanthracene Keratins Cre recombinase Integrases Tetradecanoylphorbol Acetate
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Sterneck E
Molecular Mechanisms in Development Group, Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, MD, USA.
Zhu S
Cell Signaling and Cancer Group, Department of Environmental & Molecular Toxicology, North Carolina State University, Raleigh, NC, USA.
Ramirez A
Epithelial Damage, Repair and Tissue Engineering Program, CIEMAT, Madrid, Spain.
Jorcano J L
Epithelial Damage, Repair and Tissue Engineering Program, CIEMAT, Madrid, Spain.
Smart R C
Molecular Mechanisms in Development Group, Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, MD, USA.
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Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
0950-9232
DOI
10.1038/sj.onc.1209144
Published
2006-02-23
Pages
1272-1276
Language
English
Region
England
NLM ID
8711562
PMCID
PMC3773579
Subset
IM
Grants
NCI NIH HHS · R01 CA046637 · United States
NCI NIH HHS · CA46637 · United States
External Links
PubMed source DOI: 10.1038/sj.onc.1209144 PMC Full Text View journal details
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