A Bcl-xL transgene promotes malignant conversion of chemically initiated skin papillomas.
The role of apoptosis in the pathogenesis of skin cancer was analyzed in mice bearing a Bcl-xL transgene expressed under the control of the keratin 14 promoter. No spontaneous tumors developed in the skin of these transgenic mice. Bcl-xL transgenics also failed to develop skin lesions following treatment with the chemical mutagen 9,10-dimethyl-1,2-benzanthracene, or the tumor promoter O-tetradecanoylphorbol-13-acetate. However, Bcl-xL transgenics developed a two-fold greater number of benign papillomas than control littermates following treatment with the combination of 9,10-dimethyl-1,2-benzanthracene and O-tetradecanoylphorbol-13-acetate. More significantly, Bcl-xL transgenic mice developed invasive squamous cell carcinoma earlier and more frequently than wild-type controls in response to the chemical agents. These data suggest that Bcl-xL cannot functionally substitute for a mutagenic initiator or mitogenic promoter in tumorigenesis. In contrast, Bcl-xL overexpression can dramatically increase the malignant conversion rate of benign tumors, suggesting that inhibition of apoptosis can contribute to tumor progression.
Pena
J C
JC
Gwen Knapp Center for Lupus and Immunology Research, Committee on Immunology, University of Chicago, Illinois 60637, USA.
Rudin
C M
CM
Thompson
C B
CB
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002273:Carcinogens / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D051379:Mice; D008822:Mice, Transgenic; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D019076:Transgenes; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D002273:Carcinogens; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D015127:9,10-Dimethyl-1,2-benzanthracene