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A polymorphism of the human matrix gamma-carboxyglutamic acid protein promoter alters binding of an activating protein-1 complex and is associated with altered transcription and serum levels.

Publication ,  Journal Article
Farzaneh-Far, A; Davies, JD; Braam, LA; Spronk, HM; Proudfoot, D; Chan, SW; O'Shaughnessy, KM; Weissberg, PL; Vermeer, C; Shanahan, CM
Published in: J Biol Chem
August 31, 2001

Matrix gamma-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 G-7A and T-138C polymorphisms have an important impact on in vitro promoter activity when transiently transfected into VSMCs. We found that one of these polymorphisms (T-138C) 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 T-138C 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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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

August 31, 2001

Volume

276

Issue

35

Start / End Page

32466 / 32473

Location

United States

Related Subject Headings

  • Transfection
  • Transcription, Genetic
  • Transcription Factor AP-1
  • Tetradecanoylphorbol Acetate
  • Recombinant Proteins
  • Recombinant Fusion Proteins
  • Rats, Wistar
  • Rats
  • Promoter Regions, Genetic
  • Polymorphism, Single-Stranded Conformational
 

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Farzaneh-Far, A., Davies, J. D., Braam, L. A., Spronk, H. M., Proudfoot, D., Chan, S. W., … Shanahan, C. M. (2001). A polymorphism of the human matrix gamma-carboxyglutamic acid protein promoter alters binding of an activating protein-1 complex and is associated with altered transcription and serum levels. J Biol Chem, 276(35), 32466–32473. https://doi.org/10.1074/jbc.M104909200
Farzaneh-Far, A., J. D. Davies, L. A. Braam, H. M. Spronk, D. Proudfoot, S. W. Chan, K. M. O’Shaughnessy, P. L. Weissberg, C. Vermeer, and C. M. Shanahan. “A polymorphism of the human matrix gamma-carboxyglutamic acid protein promoter alters binding of an activating protein-1 complex and is associated with altered transcription and serum levels.J Biol Chem 276, no. 35 (August 31, 2001): 32466–73. https://doi.org/10.1074/jbc.M104909200.
Farzaneh-Far A, Davies JD, Braam LA, Spronk HM, Proudfoot D, Chan SW, O’Shaughnessy KM, Weissberg PL, Vermeer C, Shanahan CM. A polymorphism of the human matrix gamma-carboxyglutamic acid protein promoter alters binding of an activating protein-1 complex and is associated with altered transcription and serum levels. J Biol Chem. 2001 Aug 31;276(35):32466–32473.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

August 31, 2001

Volume

276

Issue

35

Start / End Page

32466 / 32473

Location

United States

Related Subject Headings

  • Transfection
  • Transcription, Genetic
  • Transcription Factor AP-1
  • Tetradecanoylphorbol Acetate
  • Recombinant Proteins
  • Recombinant Fusion Proteins
  • Rats, Wistar
  • Rats
  • Promoter Regions, Genetic
  • Polymorphism, Single-Stranded Conformational