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J. Biol. Chem., Vol. 276, Issue 35, 32466-32473, August 31, 2001

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A Polymorphism of the Human Matrix -Carboxyglutamic Acid Protein Promoter Alters Binding of an Activating Protein-1 Complex and Is Associated with Altered Transcription and Serum Levels^*

Afshin Farzaneh-Far^§¶, John D. Davies^§, Levienja A. Braam, Henri M. Spronk, Diane Proudfoot, Shiu-Wan Chan, Kevin M. O'Shaughnessy^**, Peter L. Weissberg, Cees Vermeer, and Catherine M. Shanahan

From the  Division of Cardiovascular Medicine and ^** Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital (ACCI level 6), Hills Road, Cambridge CB2 2QQ, United Kingdom and the  Department of Biochemistry and Cardiovascular Research Institute, University of Maastricht, 6200 MD, Maastricht, The Netherlands

Matrix -carboxyglutamic acid protein (MGP) is a mineral-binding extracellular matrix protein synthesized by vascular smooth muscle cells (VSMCs) and chondrocytes that is thought to be a key regulator of tissue calcification. In this study, we identified four polymorphisms in the promoter region of the human MGP gene. Transfection studies showed that the G7A and T138C polymorphisms have an important impact on in vitro promoter activity when transiently transfected into VSMCs. We found that one of these polymorphisms (T138C) is significantly correlated with serum MGP levels in human subjects. Promoter deletion analysis showed that this polymorphism lies in a region of the promoter critical for transcription in VSMCs. This region contains a potential activating protein-1 (AP-1) binding element located between 142 and 136. We have demonstrated that the T138C polymorphism results in altered binding of an AP-1 complex to this region. The 138T allelic variant binds AP-1 complexes consisting primarily of c-Jun, JunB and its partners Fra-1 and Fra-2 in rat VSMC. Furthermore, the 138T variant form of the promoter was induced following phorbol 12-myristate 13-acetate treatment, while the 138C variant was refractive to phorbol 12-myristate 13-acetate treatment, confirming that AP-1 factors preferentially bind to the 138T variant. This study therefore suggests that a common polymorphism of the MGP promoter influences binding of the AP-1 complex, which may lead to altered transcription and serum levels. This could have important implications for diseases such as atherosclerosis and aortic valve stenosis, since it strongly suggests a genetic basis for regulation of tissue calcification.

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