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

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Listed:
  • Duk-Hwa Kwon

    (Chonnam National University Medical School)

  • Gwang Hyeon Eom

    (Chonnam National University Medical School)

  • Jeong Hyeon Ko

    (Chonnam National University Medical School)

  • Sera Shin

    (Chonnam National University Medical School)

  • Hosouk Joung

    (Chonnam National University Medical School)

  • Nakwon Choe

    (Chonnam National University Medical School)

  • Yoon Seok Nam

    (Chonnam National University Medical School)

  • Hyun-Ki Min

    (Chonnam National University Medical School)

  • Taewon Kook

    (Chonnam National University Medical School)

  • Somy Yoon

    (Chonnam National University Medical School)

  • Wanseok Kang

    (Chonnam University Hospital)

  • Yong Sook Kim

    (Chonnam University Hospital)

  • Hyung Seok Kim

    (Chonnam National University Medical School)

  • Hyuck Choi

    (Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University)

  • Jeong-Tae Koh

    (Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University)

  • Nacksung Kim

    (Chonnam National University Medical School)

  • Youngkeun Ahn

    (Chonnam University Hospital)

  • Hyun-Jai Cho

    (Seoul National University Hospital)

  • In-Kyu Lee

    (Kyungpook National University School of Medicine)

  • Dong Ho Park

    (Kyungpook National University School of Medicine)

  • Kyoungho Suk

    (Brain Science & Engineering Institute, Kyungpook National University School of Medicine)

  • Sang Beom Seo

    (Chung-Ang University)

  • Erin R. Wissing

    (College of Veterinary Medicine, Purdue University)

  • Susan M. Mendrysa

    (College of Veterinary Medicine, Purdue University)

  • Kwang-Il Nam

    (Chonnam National University Medical School)

  • Hyun Kook

    (Chonnam National University Medical School)

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.

Suggested Citation

  • Duk-Hwa Kwon & Gwang Hyeon Eom & Jeong Hyeon Ko & Sera Shin & Hosouk Joung & Nakwon Choe & Yoon Seok Nam & Hyun-Ki Min & Taewon Kook & Somy Yoon & Wanseok Kang & Yong Sook Kim & Hyung Seok Kim & Hyuck, 2016. "MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification," Nature Communications, Nature, vol. 7(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10492
    DOI: 10.1038/ncomms10492
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    Cited by:

    1. Zhen-Xing Wang & Zhong-Wei Luo & Fu-Xing-Zi Li & Jia Cao & Shan-Shan Rao & Yi-Wei Liu & Yi-Yi Wang & Guo-Qiang Zhu & Jiang-Shan Gong & Jing-Tao Zou & Qiang Wang & Yi-Juan Tan & Yan Zhang & Yin Hu & Yo, 2022. "Aged bone matrix-derived extracellular vesicles as a messenger for calcification paradox," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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