%0 Journal Article
%T The transcription factor ATF3 is upregulated during chondrocyte differentiation and represses cyclin D1 and A gene transcription
%A Claudine G James
%A Anita Woods
%A T Michael Underhill
%A Frank Beier
%J BMC Molecular Biology
%D 2006
%I BioMed Central
%R 10.1186/1471-2199-7-30
%X Here we demonstrate that Atf3 mRNA levels increase during mouse chondrocyte differentiation in vitro and in vivo. In addition, Atf3 mRNA levels are increased in response to cytochalasin D treatment, an inducer of chondrocyte maturation. This is accompanied by increased Atf3 promoter activity in cytochalasin D-treated chondrocytes. We had shown earlier that transcription of the cell cycle genes cyclin D1 and cyclin A in chondrocytes is dependent on CREs. Here we demonstrate that overexpression of ATF3 in primary mouse chondrocytes results in reduced transcription of both genes, as well as decreased activity of a CRE reporter plasmid. Repression of cyclin A transcription by ATF3 required the CRE in the cyclin A promoter. In parallel, ATF3 overexpression reduces the activity of a SOX9-dependent promoter and increases the activity of a RUNX2-dependent promoter.Our data suggest that transcriptional induction of the Atf3 gene in maturing chondrocytes results in down-regulation of cyclin D1 and cyclin A expression as well as activation of RUNX2-dependent transcription. Therefore, ATF3 induction appears to facilitate cell cycle exit and terminal differentiation of chondrocytes.Growth and development of endochondral bones is controlled through the highly coordinated proliferation and differentiation of growth plate chondrocytes [1-3]. These processes are regulated by a large number of endocrine, paracrine and autocrine hormones and growth factors that, to a large part, act on chondrocyte cell surface receptors. The intracellular signaling pathways mediating these effects are not completely understood; however, over the last 10 years many of the key transcriptional regulators of chondrocyte differentiation have been identified. The Sox9 gene is required for the differentiation of mesenchymal precursor cells to chondrocytes and, together with the related L-Sox5 and Sox6 proteins, controls chondrocyte-specific gene expression [4,5]. Sox9 also inhibits terminal differentiation o
%U http://www.biomedcentral.com/1471-2199/7/30