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Nat Commun. 2016 Feb 1;7:10492. doi: 10.1038/ncomms10492.

MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification.

Author information

1
Department of Pharmacology and Medical Research Center for Gene Regulation, Chonnam National University Medical School, 5 Hak-dong, Dong-ku, Gwangju 501-746, Republic of Korea.
2
Department of Cardiology, Chonnam University Hospital, Gwangju 501-757, Republic of Korea.
3
Department of Forensic Medicine, Chonnam National University Medical School, 5 Hak-dong, Dong-ku, Gwangju 501-746, Republic of Korea.
4
Department of Pharmacology and Dental Therapeutics, Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju 500-747, Republic of Korea.
5
Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
6
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 700-721, Republic of Korea.
7
Department of Ophthalmology, Kyungpook National University School of Medicine, Daegu 700-721, Republic of Korea.
8
Department of Pharmacology, Brain Science &Engineering Institute, Kyungpook National University School of Medicine, Daegu 700-721, Republic of Korea.
9
Department of Life Science, Chung-Ang University, Seoul 156-756, Republic of Korea.
10
Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.
11
Departments of Anatomy, Chonnam National University Medical School, 5 Hak-dong, Dong-ku, Gwangju 501-746, Republic of Korea.

Abstract

Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases have yet to be elucidated. Here we report that MDM2-induced ubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity via either chemical inhibitor or genetic ablation enhances VC. HDAC1 protein, but not mRNA, is reduced in cell and animal calcification models and in human calcified coronary artery. Under calcification-inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination. Overexpression of MDM2 enhances VC, whereas loss of MDM2 blunts it. Decoy peptide spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevent VC in vivo and in vitro. These results uncover a previously unappreciated ubiquitination pathway and suggest MDM2-mediated HDAC1 ubiquitination as a new therapeutic target in VC.

PMID:
26832969
PMCID:
PMC4740400
DOI:
10.1038/ncomms10492
[Indexed for MEDLINE]
Free PMC Article

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