Identification of a novel negative retinoic acid responsive element in the promoter of the human matrix Gla protein gene

Kirfel, J; Kelter, M; Cancela, LM; Price, PA; Schule, R

http://hdl.handle.net/10400.1/11683

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Abstract(s)

The vitamin K-dependent matrix Gla protein (MGP) is synthesized in a wide variety of tissues such as lung, heart, kidney, cartilage, and bone, Expression of the MGP gene is regulated by various growth factors, steroid hormones, and the vitamin A metabolite retinoic acid (RA). In this report, we present evidence that RA down-regulates MGP gene expression in different rat and human cell lines via endogenous retinoid receptors [RA receptor (RAR) and retinoid X receptor (RXR)], Repression of the human MGP (hMGP) gene is specifically mediated by ligand-activated RAR and RXR, Deletion analysis led to the identification of a novel negative response element (NRE) within the hMGP promoter, DNA binding studies performed with bacterially expressed RAR/RXR reveal the formation of a specific heterodimer/ NRE complex, Furthermore, electrophoretic mobility-shift assays performed with proteins from RA-treated cells show that endogenous RAR/RXR binds to the NRE. We demonstrate that the NRE contains a CCAAT box and that both RAR/RXR and CCAAT-binding proteins such as c/EBP beta recognize this common regulatory sequence in the hMGP promoter, Our results indicate that RA-mediated repression of the hMGP gene is due to binding of liganded RAR/RXR to a novel negative RA response element.