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 differentiation of growth plate chondrocytes. Mice deficient for the activating transcription factor 2 (ATF-2) gene show reduced proliferation of chondrocytes. Here we demonstrate that the cyclin A gene is a target of ATF-2 in chondrocytes. 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 confers regulation by ATF-2. Phosphorylation and activity of ATF-2 are enhanced dramatically upon serum stimulation of rat chondrosarcoma cells. Mutation of the CRE or overexpression of dominant-negative ATF-2 inhibits serum induction of the cyclin A promoter. Chondrocytes from ATF-2-deficient mice display reduced and delayed induction of cyclin A upon serum stimulation. The ATF-2-related transcription factor CRE-binding protein contributes to the activity 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.
Beier
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F
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Taylor
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AC
LuValle
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P
D051698:Activating Transcription Factor 2; D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D019925:Cyclin A / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010641:Phenotype; D010766:Phosphorylation; D010957:Plasmids; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D051381:Rats; D013997:Time Factors; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured
D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; C497107:Atf2 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D019925:Cyclin A; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors