Activating transcription factor 2 is necessary for maximal activity and serum induction of the cyclin A promoter in chondrocytes

Endochondral bone growth is regulated through the proliferation and differe ntiation of growth plate chondrocytes. Mice deficient for the activating tr anscription factor 2 (ATF-2) gene show reduced proliferation of chondrocyte s. Here we demonstrate that the cyclin A gene is a target of ATF-2 in chond rocytes. Serum stimulation of chondrogenic rat chondrosarcoma cells induces cyclin A expression. A cyclic AMP response element (CRE) is necessary for optimal activity and serum inducibility of the cyclin A promoter and confer s regulation by ATF-2. Phosphorylation and activity of ATF-2 are enhanced d ramatically upon serum stimulation of rat chondrosarcoma cells. Mutation of the CRE or overexpression of dominant-negative ATF-2 inhibits serum induct ion of the cyclin A promoter. Chondrocytes from ATF-2 deficient mice displa y reduced and delayed induction of cyclin A upon serum stimulation. The ATF -2-related transcription factor CRE-binding protein contributes to the acti vity of the cyclin A CRE in chondrocytes, whereas c-Jun and c-Fos regulate the promoter independently of the CRE. Our data suggest that the reduction in cyclin A levels in chondrocytes from ATF-2-deficient mice contributes to their phenotype of reduced chondrocyte proliferation and dwarfism.