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 tis sue-specific expression of different matrix metalloproteinase genes: b oth 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 irradia tion, but not by cAMP. In contrast, the expression of the 72-kDa colla genase 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 collagen ase I is induced in thymus, spleen, and, most dominantly, in bone upon overexpression of Fos. Neither collagenase IV nor stromelysin-1 or st romelysin-2 expression is affected by c-Fos. The sites of induced coll agenase 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 e nhanced levels of collagenase I transcripts were detectable. These res ults identify collagenase I as a Fos-regulated gene in vivo and sugges t a possible role for Fos/Jun heterodimers in establishing the patholo gical phenotype of c-fos transgenic mice.