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

Nature Communications
Duk-Hwa KwonHyun Kook

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.

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Citations

Mar 2, 2018·Biological Reviews of the Cambridge Philosophical Society·Xiaoxiang ChengHongjie Zhang
Sep 30, 2017·Journal of Korean Medical Science·Duk Hwa KwonHyun Kook
Sep 7, 2019·Journal of Cell Science·Jisca MajoléePeter L Hordijk
Jul 12, 2019·Experimental & Molecular Medicine·Jia GuXiangqing Kong
Jul 1, 2020·Journal of Cellular and Molecular Medicine·Jiajun ZhouChaoqing Gao
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Jan 11, 2020·Frontiers in Cell and Developmental Biology·Brian Lam, Emilie Roudier
Aug 13, 2020·Journal of Cellular and Molecular Medicine·Nakwon ChoeDuk-Hwa Kwon
May 8, 2020·International Journal of Molecular Sciences·Duk-Hwa KwonHyun Kook
Apr 12, 2019·Scientific Reports·Geon JeongYoung-Kook Kim
Mar 20, 2019·International Journal of Molecular Sciences·Somy YoonGwang Hyeon Eom
Feb 7, 2020·International Journal of Molecular Sciences·Yi-Chou HouKuo-Cheng Lu
Nov 12, 2020·Advanced Science·Li-Zhen ZhangShi-Mei Zhuang
Nov 25, 2020·Molecular Therapy. Nucleic Acids·Nakwon ChoeHyun Kook
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Dec 4, 2019·Molecular Therapy. Nucleic Acids·Juhee RyuYoung-Kook Kim

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Datasets Mentioned

BETA
GSE74755

Methods Mentioned

BETA
dissection
ubiquitination
immunoprecipitation
pull-down
PCR
immunoprecipitation assay
transfection
Assay
ELISA
Protein Assay

Software Mentioned

Genomictree
Mimics
PASW Statistics
Skyscan
Nrecon
iSolution

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