Targeted expression of bcl-2 to murine basal epidermal keratinocytes results in paradoxical retardation of ultraviolet- and chemical-induced tumorigenesis.
The antiapoptotic protein bcl-2 is found up-regulated in a number of malignant and premalignant skin conditions of keratinocyte origin, but in normal skin, it is expressed at low levels only in interfollicular epidermis. To investigate whether unregulated bcl-2 expression could affect the incidence of epidermal tumors, we have generated a mouse line that over-expresses human bcl-2 in the basal layer of epidermis under the control of the human keratin 14 promoter. These mice were subjected to both UVB photocarcinogenesis and classical two-stage chemical carcinogenesis. Although transgenic bcl-2 in these mice reduces the formation of sunburn cells after short-term UVB irradiation, chronically UVB irradiated K14/bcl-2 mice were protected against tumor development, because transgenic mice developed tumors much later and at a significantly lower frequency than controls. Immunohistochemical analyses of the UVB-induced tumors revealed no significant differences in the degree of inflammatory cell infiltrates. When either K14/bcl-2 mice or F(1) progeny of matings with mice expressing an activated Ha-ras oncogene (K14/bcl-2/ras) were treated with 9,10-dimethyl-1,2-benzanthracene/phorbol 12-myristate 13-acetate, the latency of first papilloma appearance was the same in transgenic mice and controls, but further papillomas developed more slowly in the mutant mice. Moreover, the K14/bcl-2/ras mice developed far fewer albeit larger tumors/mouse than did the ras/+ controls. The rate of conversion to malignant carcinomas, the carcinoma grade, and the frequency of lymph node metastases were not significantly different between mutants and controls. We conclude that, despite its antiapoptotic function, bcl-2, overexpressed in basal epidermal keratinocytes, exerts a paradoxical retardation on the development of skin tumors induced by chemical carcinogens and particularly by UVB.
Rossiter
H
H
Department of Dermatology, University of Vienna Medical School, Vienna, A-1090, Austria.
Beissert
S
S
Mayer
C
C
Schön
M P
MP
Wienrich
B G
BG
Tschachler
E
E
Kupper
T S
TS
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D011905:Genes, ras / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D010212:Papilloma / Q000209:etiology / Q000517:prevention & control*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012878:Skin Neoplasms / Q000209:etiology / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D014466:Ultraviolet Rays / Q000009:adverse effects
D002273:Carcinogens; D019253:Proto-Oncogene Proteins c-bcl-2; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate