Fig. 5.

Transcriptional and post-transcriptional regulation of the CCN2 gene in chondrocytes. Transcriptional regulation observed in chondrocytes or chondrocytic cells is summarized in the upper-half, while post-transcriptional regulation is schematized in the lower half. TGF-β is known to enhance the CCN2 expression in chondrocytes, as well as in a number of other types of cells. This regulation is supposedly mediated by 3 genetic cis-elements: Smad-binding element (SBE), basal control element (BCE), and Ets1-binding sequence in the proximal promoter, directly or indirectly through endothelin-1 (ET-1). Hatched arrows indicate the actions experimentally indicated from studies using non-chondrocytic cells. MMP-3 is shown to directly bind to TRENDIC to enhance transcription. The RNA stability and translation of the CCN2 mRNA is regulated by direct interaction with nucleophosmin (NPM) and miR-18a through their specific targets in the 3′-untranslated region (UTR). The cis-acting element of structure-anchored repression (CAESAR) mediates the post-transcriptional regulation by factor(s) yet to be identified. TATA, ORF and AAAAA represent the TATA box, open reading frame and polyadenyl tail, respectively