Resistance to skin tumorigenesis in DNAPK-deficient SCID mice is not due to immunodeficiency but results from hypersensitivity to TPA-induced apoptosis.
Scid/scid mice have a mutation in the gene encoding the catalytic subunit of DNA-dependent protein kinase (DNAPK(cs)) and are defective in end joining of DNA double-strand breaks. As a consequence, they are radiosensitive, lack mature T and B lymphocytes and are predisposed to lymphomagenesis. To determine if this DNA repair defect also increased predisposition to skin tumor formation, we treated the dorsal skin of scid/scid mice with the carcinogen 7,12-dimethylbenz[a]anthracene followed by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Contrary to expectations, we observed a 5-fold reduction in skin tumor multiplicity in scid/scid mice. We addressed whether this was related to their immunodeficiency by similarly treating Rag1(-/-) and Rag2(-/-) knockout mice which also lack mature T and B lymphocytes. We observed no difference in skin tumor multiplicity for either strain compared with control littermates. This indicates a lack of a significant role for T or B lymphocyte mediated immunity on either papilloma or carcinoma formation. We observed a significant increase in apoptotic and necrotic cell death in follicular and interfollicular epithelial cells of scid/scid mice following TPA treatment. This hypersensitivity of SCID (severe combined immunodeficient) cells to TPA indicates that the resistance to skin tumor formation in scid/scid mice is due to loss of initiated cells through TPA-induced cell killing.
Kemp
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CJ
Fred Hutchinson Cancer Research Center C1-015, 1100 Fairview Avenue North, PO Box 19024, Seattle, WA 98109-1024, USA. cjkemp@fhcrc.org
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases; D013755:Tetradecanoylphorbol Acetate