title: Ubiquitin carboxyl terminal hydrolyase L1-suppressed autophagic degradation of p21WAF1/Cip1 as a novel feedback mechanism in the control of cardiac fibroblast proliferation.
abstract: OBJECTIVE
  Deubiquitinating enzymes (DUBs) appear to be critical regulators of a multitude of processes such as proliferation, apoptosis, differentiation, and inflammation; however, the potential roles of DUBs in the heart remain to be determined. This study was aimed to explore the role of a DUB, ubiquitin carboxyl terminal hydrolyase L1 (UCH-L1) in maladaptive cardiac remodeling and dysfunction.
  
  
  RESULTS
  Maladaptive cardiac remodeling and dysfunction were induced in mice by transverse aortic constriction (TAC). UCH-L1 expression was transiently increased and then declined near to the basal level while impairment of cardiac function proceeded. The upregulation of UCH-L1 was observed in cardiac myocytes and fibroblasts. In primary culture of cardiac fibroblasts, UCH-L1 was upregulated by platelet-derived growth factor (PDGF)-BB and PDGF-DD. Adenoviral overexpession of UCH-L1 inhibited the PDGF-induced cardiac fibroblast proliferation without affecting the activation of mitogen activated protein kinases (MAPKs), Akt, and signal transducers and activators of transcription 3 (STAT3). Further signaling dissection revealed that PDGF-BB posttranscriptional upregulated p21WAF1/Cip1 protein expression, which was inhibited by rapamycin, an activator of autophagy via suppressing mammalian target of rapamycin (mTOR), rather than MG132, a proteasome inhibitor. Overexpression of UCH-L1 enhanced PDGF-BB-induced mTOR phosphorylation and upregulation of p21WAF1/Cip1 protein expression while suppressed autophagic flux in cardiac fibroblasts.
  
  
  CONCLUSIONS
  UCH-L1 facilitates PDGF-BB-induced suppression of autophagic degradation of p21WAF1/Cip1 proteins in cardiac fibroblasts, which may serve as a novel negative feedback mechanism in the control of cardiac fibroblast proliferation contributing to cardiac fibrosis and dysfunction.
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, Shandong, China; Department of Pathophysiology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Guo
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Niu
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shao
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Huanjie
authors.initials: H
authors.lastname: Li
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Linmao
authors.initials: L
authors.lastname: Lv
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Qin
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, Shandong, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America.
authors.forename: Dongqi
authors.initials: D
authors.lastname: Tang
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Xing Li
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, Shandong, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America.
authors.forename: Taixing
authors.initials: T
authors.lastname: Cui
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001011:Aorta / Q000473:pathology; D001343:Autophagy; D000077214:Becaplermin; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005434:Flow Cytometry; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D012844:Sincalide / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D015854:Up-Regulation; D020257:Ventricular Remodeling
chemical_list: D000077214:Becaplermin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D050796:STAT3 Transcription Factor; D012844:Sincalide; D043222:Ubiquitin Thiolesterase; C493957:Cdkn1a protein, mouse; C498951:Pdgfd protein, mouse; C494087:Stat3 protein, mouse; C496976:Uchl1 protein, mouse
references.citation: PLoS One. 2009 Jun 18;4(6):e5955
references.pmid: 19536331
references.citation: Exp Anim. 2007 Apr;56(2):71-7
references.pmid: 17460351
references.citation: Transgenic Res. 2010 Oct;19(5):799-808
references.pmid: 20069454
references.citation: BMC Biochem. 2008 Oct 21;9 Suppl 1:S3
references.pmid: 19007433
references.citation: Science. 1989 Nov 3;246(4930):670-3
references.pmid: 2530630
references.citation: J Biol Chem. 2008 Aug 29;283(35):23731-8
references.pmid: 18550537
references.citation: Mol Cell. 2013 Aug 8;51(3):283-96
references.pmid: 23911927
references.citation: Arterioscler Thromb Vasc Biol. 2007 Oct;27(10):2184-90
references.pmid: 17690318
references.citation: Biochem Biophys Res Commun. 2009 May 1;382(2):451-6
references.pmid: 19289106
references.citation: Circ Res. 2010 Jun 11;106(11):1675-80
references.pmid: 20538689
references.citation: J Biol Chem. 2012 Aug 31;287(36):30063-72
references.pmid: 22798074
references.citation: Cell Signal. 2009 Oct;21(10):1513-21
references.pmid: 19477270
references.citation: Biochim Biophys Acta. 2008 Dec;1782(12):749-63
references.pmid: 18634872
references.citation: Biochem Biophys Res Commun. 2010 Jan 1;391(1):852-6
references.pmid: 19945429
references.citation: Circ Res. 2002 Dec 13;91(12):1103-13
references.pmid: 12480810
references.citation: J Biol Chem. 2013 May 3;288(18):12615-26
references.pmid: 23543736
references.citation: Circ Res. 2006 Dec 8;99(12):1315-28
references.pmid: 17158347
references.citation: BMC Urol. 2011 Aug 24;11:19
references.pmid: 21864408
references.citation: Nature. 2006 Oct 19;443(7113):780-6
references.pmid: 17051204
references.citation: Genes Dev. 1999 Jun 15;13(12):1501-12
references.pmid: 10385618
references.citation: Circ Res. 2005 Nov 11;97(10):1036-45
references.pmid: 16224065
references.citation: PLoS One. 2009 Aug 26;4(8):e6764
references.pmid: 19707515
references.citation: J Pharmacol Exp Ther. 2005 Jun;313(3):952-61
references.pmid: 15769867
references.citation: Annu Rev Biochem. 2009;78:363-97
references.pmid: 19489724
references.citation: Nat Rev Mol Cell Biol. 2009 May;10(5):319-31
references.pmid: 19352404
references.citation: Circulation. 2007 Apr 10;115(14):1885-94
references.pmid: 17389268
references.citation: Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1843-50
references.pmid: 19592468
references.citation: Cell. 2010 Feb 5;140(3):313-26
references.pmid: 20144757
references.citation: Cell. 2005 Dec 2;123(5):773-86
references.pmid: 16325574
references.citation: Physiol Rev. 2002 Apr;82(2):373-428
references.pmid: 11917093
references.citation: Mod Pathol. 2003 Oct;16(10):963-9
references.pmid: 14559978
references.citation: J Mol Cell Cardiol. 2006 Oct;41(4):567-79
references.pmid: 16949602
references.citation: Mol Endocrinol. 2002 Sep;16(9):2113-23
references.pmid: 12198247
references.citation: Science. 2007 Jan 12;315(5809):201-5
references.pmid: 17218518
references.citation: Circulation. 2007 Mar 20;115(11):1456-63
references.pmid: 17372187
references.citation: Mol Cell. 2011 Oct 21;44(2):304-16
references.pmid: 22017876
references.citation: Nat Immunol. 2012 Jan 29;13(3):255-63
references.pmid: 22286270
references.citation: Neurochem Int. 2007 Jul-Sep;51(2-4):105-11
references.pmid: 17586089
references.citation: Circulation. 2003 Aug 12;108(6):664-7
references.pmid: 12900338
references.citation: Mol Cell Biol. 2013 Mar;33(6):1188-97
references.pmid: 23297343
references.citation: Chem Biol. 2003 Sep;10(9):837-46
references.pmid: 14522054
references.citation: Cell. 2006 Feb 10;124(3):471-84
references.pmid: 16469695
references.citation: J Biol Chem. 2012 Apr 6;287(15):12455-68
references.pmid: 22362782
references.citation: Genes Dev. 2008 May 15;22(10):1276-312
references.pmid: 18483217
references.citation: Circ Res. 2007 May 11;100(9):1276-91
references.pmid: 17495234