Conditional ablation of C/EBP beta demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis.
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.
Sterneck
E
E
Molecular Mechanisms in Development Group, Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, MD, USA.
Zhu
S
S
Cell Signaling and Cancer Group, Department of Environmental & Molecular Toxicology, North Carolina State University, Raleigh, NC, USA.
Ramirez
A
A
Epithelial Damage, Repair and Tissue Engineering Program, CIEMAT, Madrid, Spain.
Jorcano
J L
JL
Epithelial Damage, Repair and Tissue Engineering Program, CIEMAT, Madrid, Spain.
Smart
R C
RC
Molecular Mechanisms in Development Group, Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, MD, USA.
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000502:physiology*; D002273:Carcinogens / Q000633:toxicity; D005260:Female; D019426:Integrases / Q000378:metabolism; D053569:Keratin-15; D053555:Keratin-5; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology*; D007633:Keratins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D022782:CCAAT-Enhancer-Binding Protein-beta; D002273:Carcinogens; D053569:Keratin-15; D053555:Keratin-5; C492053:Krt15 protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; D007633:Keratins; C045073:Cre recombinase; D019426:Integrases; D013755:Tetradecanoylphorbol Acetate