title: MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification.
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.
authors.affiliation: 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.
authors.forename: Duk-Hwa
authors.initials: DH
authors.lastname: Kwon
authors.affiliation: 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.
authors.forename: Gwang Hyeon
authors.initials: GH
authors.lastname: Eom
authors.affiliation: 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.
authors.forename: Jeong Hyeon
authors.initials: JH
authors.lastname: Ko
authors.affiliation: 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.
authors.forename: Sera
authors.initials: S
authors.lastname: Shin
authors.affiliation: 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.
authors.forename: Hosouk
authors.initials: H
authors.lastname: Joung
authors.affiliation: 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.
authors.forename: Nakwon
authors.initials: N
authors.lastname: Choe
authors.affiliation: 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.
authors.forename: Yoon Seok
authors.initials: YS
authors.lastname: Nam
authors.affiliation: 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.
authors.forename: Hyun-Ki
authors.initials: HK
authors.lastname: Min
authors.affiliation: 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.
authors.forename: Taewon
authors.initials: T
authors.lastname: Kook
authors.affiliation: 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.
authors.forename: Somy
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Department of Cardiology, Chonnam University Hospital, Gwangju 501-757, Republic of Korea.
authors.forename: Wanseok
authors.initials: W
authors.lastname: Kang
authors.affiliation: Department of Cardiology, Chonnam University Hospital, Gwangju 501-757, Republic of Korea.
authors.forename: Yong Sook
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Forensic Medicine, Chonnam National University Medical School, 5 Hak-dong, Dong-ku, Gwangju 501-746, Republic of Korea.
authors.forename: Hyung Seok
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Dental Therapeutics, Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju 500-747, Republic of Korea.
authors.forename: Hyuck
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Pharmacology and Dental Therapeutics, Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju 500-747, Republic of Korea.
authors.forename: Jeong-Tae
authors.initials: JT
authors.lastname: Koh
authors.affiliation: 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.
authors.forename: Nacksung
authors.initials: N
authors.lastname: Kim
authors.affiliation: Department of Cardiology, Chonnam University Hospital, Gwangju 501-757, Republic of Korea.
authors.forename: Youngkeun
authors.initials: Y
authors.lastname: Ahn
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Hyun-Jai
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 700-721, Republic of Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology, Kyungpook National University School of Medicine, Daegu 700-721, Republic of Korea.
authors.forename: Dong Ho
authors.initials: DH
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Brain Science &Engineering Institute, Kyungpook National University School of Medicine, Daegu 700-721, Republic of Korea.
authors.forename: Kyoungho
authors.identifier: http://orcid.org/0000-0002-9555-4203
authors.initials: K
authors.lastname: Suk
authors.affiliation: Department of Life Science, Chung-Ang University, Seoul 156-756, Republic of Korea.
authors.forename: Sang Beom
authors.initials: SB
authors.lastname: Seo
authors.affiliation: Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Erin R
authors.initials: ER
authors.lastname: Wissing
authors.affiliation: Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Mendrysa
authors.affiliation: Departments of Anatomy, Chonnam National University Medical School, 5 Hak-dong, Dong-ku, Gwangju 501-746, Republic of Korea.
authors.forename: Kwang-Il
authors.initials: KI
authors.lastname: Nam
authors.affiliation: 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.
authors.forename: Hyun
authors.initials: H
authors.lastname: Kook
mesh_terms: D000818:Animals; D002118:Calcium; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D054875:Ubiquitination; D061205:Vascular Calcification / Q000378:metabolism*
chemical_list: C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C110550:HDAC1 protein, human; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D002118:Calcium
references.citation: J Bone Miner Res. 2005 Dec;20(12):2254-63
references.pmid: 16294278
references.citation: Circulation. 2006 Jan 3;113(1):51-9
references.pmid: 16380549
references.citation: Nat Rev Cancer. 2006 Jan;6(1):38-51
references.pmid: 16397526
references.citation: J Cell Biol. 2006 Mar 13;172(6):909-21
references.pmid: 16533949
references.citation: J Clin Invest. 2007 Sep;117(9):2459-67
references.pmid: 17786239
references.citation: Mol Cell Biochem. 2008 Jan;308(1-2):25-33
references.pmid: 17909945
references.citation: FASEB J. 2008 Oct;22(10):3549-60
references.pmid: 18606865
references.citation: Arterioscler Thromb Vasc Biol. 2000 Feb;20(2):317-27
references.pmid: 10669626
references.citation: Nat Biotechnol. 2000 Mar;18(3):300-3
references.pmid: 10700145
references.citation: J Biol Chem. 2000 Mar 24;275(12):8945-51
references.pmid: 10722742
references.citation: Am J Kidney Dis. 2001 Oct;38(4 Suppl 1):S34-7
references.pmid: 11576919
references.citation: Arterioscler Thromb Vasc Biol. 2001 Oct;21(10):1610-6
references.pmid: 11597934
references.citation: EMBO J. 2002 Jun 3;21(11):2672-81
references.pmid: 12032080
references.citation: Circulation. 2002 Jun 4;105(22):2686-91
references.pmid: 12045177
references.citation: J Clin Invest. 2003 Sep;112(6):863-71
references.pmid: 12975471
references.citation: Science. 2004 Feb 6;303(5659):844-8
references.pmid: 14704432
references.citation: Arterioscler Thromb Vasc Biol. 2004 Jul;24(7):1161-70
references.pmid: 15155384
references.citation: Am J Cardiol. 1970 Sep;26(3):241-7
references.pmid: 5505449
references.citation: Exp Cell Res. 1976 Mar 15;98(2):349-66
references.pmid: 943301
references.citation: Am J Pathol. 1989 Apr;134(4):947-54
references.pmid: 2495727
references.citation: Nature. 1992 Jul 2;358(6381):80-3
references.pmid: 1614537
references.citation: Circulation. 1992 Jul;86(1):64-70
references.pmid: 1617791
references.citation: Nature. 1997 Mar 6;386(6620):78-81
references.pmid: 9052783
references.citation: Cell. 1997 May 30;89(5):747-54
references.pmid: 9182762
references.citation: J Mol Cell Cardiol. 1997 Aug;29(8):2107-24
references.pmid: 9281443
references.citation: Nature. 1997 Nov 6;390(6655):45-51
references.pmid: 9363890
references.citation: Cardiovasc Res. 1997 Oct;36(1):118-26
references.pmid: 9415280
references.citation: Genes Dev. 1998 May 1;12(9):1260-8
references.pmid: 9573043
references.citation: Am J Pathol. 1999 Mar;154(3):671-5
references.pmid: 10079244
references.citation: Oncogene. 1999 Mar 18;18(11):1935-44
references.pmid: 10208415
references.citation: Nucleic Acids Res. 2005;33(1):13-26
references.pmid: 15640443
references.citation: Nat Rev Mol Cell Biol. 2005 Aug;6(8):610-21
references.pmid: 16064137
references.citation: Mol Cancer Ther. 2005 Sep;4(9):1369-77
references.pmid: 16170029
references.citation: Circulation. 2005 Nov 1;112(18):2875-82
references.pmid: 16267260
references.citation: Circulation. 2006 Jun 6;113(22):2579-88
references.pmid: 16735673
references.citation: Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1423-30
references.pmid: 16601233
references.citation: Mol Cell Biol. 2006 Sep;26(17):6502-10
references.pmid: 16914734
references.citation: Mol Endocrinol. 2006 Oct;20(10):2432-43
references.pmid: 16728531
references.citation: J Neurosci. 2007 May 30;27(22):5967-75
references.pmid: 17537967
references.citation: Genes Dev. 2007 Jul 15;21(14):1790-802
references.pmid: 17639084
references.citation: Am J Physiol Heart Circ Physiol. 2007 Aug;293(2):H968-77
references.pmid: 17400721
references.citation: Cardiovasc Res. 2008 Dec 1;80(3):416-24
references.pmid: 18697792
references.citation: Nat Cell Biol. 2009 Mar;11(3):295-302
references.pmid: 19182791
references.citation: Proc Natl Acad Sci U S A. 2009 May 12;106(19):7751-5
references.pmid: 19416910
references.citation: Annu Rev Biochem. 2009;78:399-434
references.pmid: 19489725
references.citation: Am J Physiol Heart Circ Physiol. 2009 Oct;297(4):H1535-43
references.pmid: 19684185
references.citation: Am J Physiol Lung Cell Mol Physiol. 2009 Nov;297(5):L864-70
references.pmid: 19700647
references.citation: EMBO Rep. 2009 Nov;10(11):1250-8
references.pmid: 19798103
references.citation: Nat Cell Biol. 2010 Feb;12(2):132-42
references.pmid: 20081843
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10038-43
references.pmid: 20479273
references.citation: J Bone Miner Res. 2011 Jul;26(7):1411-24
references.pmid: 21308777
references.citation: Cell Cycle. 2012 Apr 1;11(7):1393-9
references.pmid: 22421142
references.citation: Circulation. 2012 May 8;125(18):2243-55
references.pmid: 22492635
references.citation: Circ Res. 2012 Jul 6;111(2):e19-31
references.pmid: 22647876
references.citation: Circ Res. 2012 Aug 17;111(5):543-52
references.pmid: 22773442
references.citation: J Immunol. 2013 Feb 15;190(4):1623-30
references.pmid: 23303667
references.citation: PLoS Biol. 2013;11(4):e1001534
references.pmid: 23585735
references.citation: Cancer Res. 2013 Apr 15;73(8):2587-97
references.pmid: 23400593
references.citation: J Atheroscler Thromb. 2013;20(6):538-47
references.pmid: 23518467
references.citation: J Mol Cell Cardiol. 2014 Feb;67:112-25
references.pmid: 24374140
references.citation: Circ Res. 2014 Mar 28;114(7):1133-43
references.pmid: 24526703
references.citation: Gene Ther. 2014 Apr;21(4):353-62
references.pmid: 24500526