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

• Published in: The Journal of biological chemistry 1994-04, Vol.269 (14), p.10363-10369
• Main Authors: GACK, S, VALLON, R, SCHAPER, J, RÜTHER, U, ANGEL, P
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Base Sequence; Biological and medical sciences; Bone Neoplasms - enzymology; Carcinogens - pharmacology; Cell Line, Transformed; Cloning, Molecular; Collagenases - biosynthesis; Collagenases - genetics; Cyclic AMP - pharmacology; DNA, Complementary; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; Gene Expression - radiation effects; Matrix Metalloproteinase 10; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Metalloendopeptidases - biosynthesis; Metalloendopeptidases - genetics; Mice; Mice, Transgenic; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Phenotype; Proto-Oncogene Proteins c-fos - physiology; Tetradecanoylphorbol Acetate - pharmacology; Transcription. Transcription factor. Splicing. Rna processing; Ultraviolet Rays
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(17)34069-3

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.