Inhibition of CCAAT/enhancer binding protein family DNA binding in mouse epidermis prevents and regresses papillomas.
The CCAAT/enhancer binding proteins (C/EBP) are a family of B-ZIP DNA binding proteins that act as transcription factors to regulate growth and differentiation of many cell types, including keratinocytes. To examine the consequences of inhibiting the C/EBP family of transcription factors in skin, we generated transgenic mice that use the tetracycline system to conditionally express A-C/EBP, a dominant negative that inhibits the DNA binding of C/EBP family members. We expressed A-C/EBP in the basal layer of the skin epidermis during a two-step skin carcinogenesis protocol. A-C/EBP expression caused hyperplasia of the basal epidermis and increased apoptosis in the suprabasal epidermis. The mice developed fewer papillomas and had systemic hair loss. A-C/EBP expression caused C/EBPbeta protein to disappear whereas C/EBPalpha, p53, Bax, and caspase-3 protein levels were dramatically up-regulated in the suprabasal layer. Primary keratinocytes recapitulate the A-C/EBP induction of cell growth and increase in p53 protein. A-C/EBP expression after papilloma development caused the papillomas to regress with an associated increase in apoptosis and up-regulation of p53 protein. Furthermore, A-C/EBP-expressing mice heterozygous for p53 were more susceptible to papilloma formation, suggesting that the suppression of papilloma formation has a p53-dependent mechanism. These results implicate DNA binding of C/EBP family members as a potential molecular therapeutic target.
Oh
Won Jun
WJ
Laboratory of Metabolism, National Cancer Institute, Center for Cancer Research/NIH, Bethesda, MD 20892, USA.
Rishi
Vikas
V
Orosz
Andras
A
Gerdes
Michael J
MJ
Vinson
Charles
C
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D004247:DNA / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010212:Papilloma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D022762:CCAAT-Enhancer-Binding Proteins; D004247:DNA