Phenotypic alterations in fos-transgenic mice correlate with changes in Fos/Jun-dependent collagenase type I expression. Regulation of mouse metalloproteinases by carcinogens, tumor promoters, cAMP, and Fos oncoprotein.
Using specific cDNAs isolated from mouse fibroblasts we determined tissue-specific expression of different matrix metalloproteinase genes: both stromelysin-1 and collagenase IV are highly expressed in heart and lung, whereas collagenase I is expressed most abundantly in skeletal muscle, kidney, and bone. High basal level expression of stromelysin-2 is found in heart and kidney. Like in man and rat, the expressions of collagenase I, stromelysin-1, and stromelysin-2 are regulated by the tumor promoter 12-O-tetradecanoyl-phorbol 13-acetate and by UV irradiation, but not by cAMP. In contrast, the expression of the 72-kDa collagenase IV is not affected by either stimuli. We and others have shown previously that under cell culture conditions, the regulation of human collagenase I is regulated by the transcription factor Fos/Jun (AP-1). Here we show that in c-fos transgenic mice transcription of collagenase I is induced in thymus, spleen, and, most dominantly, in bone upon overexpression of Fos. Neither collagenase IV nor stromelysin-1 or stromelysin-2 expression is affected by c-Fos. The sites of induced collagenase I expression correlate with the sites of Fos-induced long-term cellular alterations in transgenic mice including bone remodeling and T cell development. In fact, in the developing bone tumors strongly enhanced levels of collagenase I transcripts were detectable. These results identify collagenase I as a Fos-regulated gene in vivo and suggest a possible role for Fos/Jun heterodimers in establishing the pathological phenotype of c-fos transgenic mice.
Gack
S
S
Kernforschungszentrum Karlsruhe, Institut für Genetik, Federal Republic of Germany.
Vallon
R
R
Schaper
J
J
Rüther
U
U
Angel
P
P
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001859:Bone Neoplasms / Q000201:enzymology; D002273:Carcinogens / Q000494:pharmacology*; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D017364:Collagenases / Q000096:biosynthesis / Q000235:genetics; D000242:Cyclic AMP / Q000494:pharmacology*; D018076:DNA, Complementary; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D053506:Matrix Metalloproteinase 10; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014466:Ultraviolet Rays
D002273:Carcinogens; D018076:DNA, Complementary; D016760:Proto-Oncogene Proteins c-fos; D000242:Cyclic AMP; D017364:Collagenases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D053506:Matrix Metalloproteinase 10; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate