Inhibition of CREB function in mouse epidermis reduces papilloma formation.
We used a double transgenic tetracycline system to conditionally express A-CREB, a dominant negative protein that prevents the DNA binding and function of cAMP-responsive element binding protein (CREB) family members, in mouse basal epidermis using the keratin 5 promoter. There was no phenotype in the adult. However, following a 7,12-dimethylbenz(a)anthracene (DMBA)/phorbol-12-myristate-13-acetate two-stage skin carcinogenesis experiment, A-CREB-expressing epidermis develop 5-fold fewer papillomas than wild-type controls. However, A-CREB expression one month after DMBA treatment does not prevent papilloma formation, suggesting that CREB functions at an early stage of papilloma formation. Oncogenic H-Ras genes with A-->T mutations in codon 61 were found in wild-type skin but not in A-CREB-expressing skin 2 days after DMBA treatment, suggesting that A-CREB either prevents DMBA mutagenesis or kills oncogenic H-Ras cells. In primary keratinocyte cultures, A-CREB expression induced apoptosis of v-Ras(Ha)-infected cells and suppressed the expression of cell cycle proteins cyclin B1 and cyclin D1. These results suggest that inhibiting CREB function is a valuable cancer prevention strategy.
Laboratory of Metabolism, National Cancer Institute, NIH, 37 Convent Drive, Room 2D24, Bethesda, MD 20892, USA.
Julian
J
Rozenberg
Vikas
V
Rishi
Andras
A
Orosz
Jaideep
J
Moitra
Adam
A
Glick
Charles
C
Vinson
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D011905:Genes, ras / Q000235:genetics; D020287:In Situ Nick-End Labeling; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009154:Mutation; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D002273:Carcinogens; D017362:Cyclic AMP Response Element-Binding Protein; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate