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KMID : 0620920210530111781
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Experimental & Molecular Medicine
2021 Volume.53 No. 11 p.1781 ~ p.1791
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Regulation of MDM2 E3 ligase-dependent vascular calcification by MSX1/2
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Kwon Duk-Hwa
Choe Nak-Won
Shin Se-Ra
Ryu Ju-Hee
Kim Nack-Sung
Eom Gwang-Hyeon
Nam Kwang-Il
Kim Hyung-Seok
Ahn Young-Keun
Kim Young-Kook
Park Woo-Jin
Mendrysa Susan M.
Kook Hyun
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Abstract
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Vascular calcification increases morbidity and mortality in patients with cardiovascular and renal diseases. Previously, we reported that histone deacetylase 1 prevents vascular calcification, whereas its E3 ligase, mouse double minute 2 homolog (MDM2), induces vascular calcification. In the present study, we identified the upstream regulator of MDM2. By utilizing cellular models and transgenic mice, we confirmed that E3 ligase activity is required for vascular calcification. By promoter analysis, we found that both msh homeobox 1 (Msx1) and msh homeobox 2 (Msx2) bound to the MDM2 promoter region, which resulted in transcriptional activation of MDM2. The expression levels of both Msx1 and Msx2 were increased in mouse models of vascular calcification and in calcified human coronary arteries. Msx1 and Msx2 potentiated vascular calcification in cellular and mouse models in an MDM2-dependent manner. Our results establish a novel role for MSX1/MSX2 in the transcriptional activation of MDM2 and the resultant increase in MDM2 E3 ligase activity during vascular calcification.
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KEYWORD
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Disease model, Gene regulation
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