title: Back to your heart: ubiquitin proteasome system-regulated signal transduction.
abstract: Awareness of the regulation of cell signaling by post-translational ubiquitination has emerged over the past 2 decades. Like phosphorylation, post-translational modification of proteins with ubiquitin can result in the regulation of numerous cellular functions, for example, the DNA damage response, apoptosis, cell growth, and the innate immune response. In this review, we discuss recently published mechanisms by which the ubiquitin proteasome system regulates key signal transduction pathways in the heart, including MAPK JNK, calcineurin, FOXO, p53, and estrogen receptors α and β. We then explore how ubiquitin proteasome system-specific regulation of these signal transduction pathways plays a role in the pathophysiology of common cardiac diseases, such as cardiac hypertrophy, heart failure, ischemia reperfusion injury, and diabetes. This article is part of a Special Section entitled "Post-translational Modification."
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Portbury
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Ronnebaum
authors.forename: Makhosazane
authors.initials: M
authors.lastname: Zungu
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006321:Heart / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System; D009206:Myocardium / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D051858:Forkhead Transcription Factors; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D019703:Calcineurin; D046988:Proteasome Endopeptidase Complex
references.citation: J Biol Chem. 1997 Aug 8;272(32):19943-50
references.pmid: 9242662
references.citation: Mol Endocrinol. 1999 Sep;13(9):1522-34
references.pmid: 10478843
references.citation: Circ Res. 2008 Feb 1;102(2):e20-35
references.pmid: 18202312
references.citation: FEBS Lett. 2008 Dec 10;582(29):4008-14
references.pmid: 19026640
references.citation: Science. 2004 Feb 27;303(5662):1371-4
references.pmid: 14739464
references.citation: J Biol Chem. 1998 Mar 27;273(13):7228-34
references.pmid: 9516415
references.citation: Endocrinology. 2005 Oct;146(10):4370-6
references.pmid: 16020479
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20517-22
references.pmid: 18077353
references.citation: Cell Metab. 2008 Feb;7(2):101-3
references.pmid: 18249169
references.citation: Mol Cell Biol. 2000 Nov;20(22):8458-67
references.pmid: 11046142
references.citation: Brain Res Mol Brain Res. 2004 Apr 7;123(1-2):27-36
references.pmid: 15046863
references.citation: Cancer Res. 2000 Apr 15;60(8):2247-52
references.pmid: 10786691
references.citation: Circ Res. 2002 May 17;90(9):1004-11
references.pmid: 12016267
references.citation: Diabetes. 2005 Feb;54(2):554-62
references.pmid: 15677515
references.citation: Nat Rev Mol Cell Biol. 2001 Mar;2(3):195-201
references.pmid: 11265249
references.citation: Genes Dev. 2010 Aug 1;24(15):1580-9
references.pmid: 20679392
references.citation: J Clin Invest. 2004 Oct;114(8):1058-71
references.pmid: 15489953
references.citation: J Biol Chem. 2001 Jul 27;276(30):27936-43
references.pmid: 11369780
references.citation: Trends Cardiovasc Med. 2010 Apr;20(3):73-8
references.pmid: 21130949
references.citation: Cell. 2004 Apr 16;117(2):225-37
references.pmid: 15084260
references.citation: FASEB J. 2006 Feb;20(2):362-4
references.pmid: 16371426
references.citation: Rev Esp Anestesiol Reanim. 1975 Jan;22(1):1-35
references.pmid: 1144892
references.citation: Genes Dev. 1998 Aug 15;12(16):2499-509
references.pmid: 9716403
references.citation: Cell. 2005 Jul 1;121(7):1071-83
references.pmid: 15989956
references.citation: FEBS Lett. 2005 Sep 12;579(22):5007-12
references.pmid: 16122737
references.citation: Oxid Med Cell Longev. 2009 Jul-Aug;2(3):119-29
references.pmid: 20592766
references.citation: Mol Cell Biol. 2004 May;24(10):4184-95
references.pmid: 15121840
references.citation: J Surg Res. 2003 Dec;115(2):325-44
references.pmid: 14697301
references.citation: Biochem Biophys Res Commun. 1996 Jan 5;218(1):83-8
references.pmid: 8573181
references.citation: J Mol Cell Cardiol. 2006 Apr;40(4):451-4
references.pmid: 16481005
references.citation: J Biol Chem. 2007 Jul 27;282(30):21945-52
references.pmid: 17525155
references.citation: Mol Cancer Res. 2006 Jan;4(1):15-25
references.pmid: 16446403
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7421-6
references.pmid: 10377430
references.citation: J Biol Chem. 2008 Dec 19;283(51):35464-73
references.pmid: 18815134
references.citation: Science. 1998 Sep 11;281(5383):1671-4
references.pmid: 9733513
references.citation: J Biol Chem. 2009 Feb 27;284(9):5488-96
references.pmid: 19117950
references.citation: Proc Natl Acad Sci U S A. 1992 May 1;89(9):4037-41
references.pmid: 1570330
references.citation: Science. 2004 Feb 27;303(5662):1374-8
references.pmid: 14739463
references.citation: Physiol Rev. 2010 Oct;90(4):1507-46
references.pmid: 20959622
references.citation: Endocrinology. 2008 Jul;149(7):3361-9
references.pmid: 18372323
references.citation: J Mol Cell Cardiol. 2005 Feb;38(2):289-97
references.pmid: 15698835
references.citation: Shock. 2000 Aug;14(2):81-90
references.pmid: 10947147
references.citation: Nat Immunol. 2002 Mar;3(3):281-7
references.pmid: 11828324
references.citation: Mol Cell Biol. 2001 May;21(10):3534-46
references.pmid: 11313479
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10188-93
references.pmid: 16006521
references.citation: Endocrinology. 1984 Feb;114(2):629-37
references.pmid: 6690295
references.citation: Exp Cell Res. 2010 Oct 15;316(17):2903-9
references.pmid: 20633551
references.citation: Circulation. 2004 Nov 16;110(20):3270-5
references.pmid: 15533858
references.citation: Nature. 2007 Mar 22;446(7134):444-8
references.pmid: 17334357
references.citation: Cell. 2007 Jan 12;128(1):141-56
references.pmid: 17218261
references.citation: Nature. 2000 May 4;405(6782):91-4
references.pmid: 10811224
references.citation: Am J Physiol Regul Integr Comp Physiol. 2010 Jun;298(6):R1597-606
references.pmid: 20375266
references.citation: Circ Res. 1996 Aug;79(2):162-73
references.pmid: 8755992
references.citation: Cardiovasc Res. 2010 Dec 1;88(3):424-33
references.pmid: 20601385
references.citation: PLoS One. 2008 Jul 30;3(7):e2819
references.pmid: 18665269
references.citation: Am J Physiol Heart Circ Physiol. 2005 Jun;288(6):H2836-42
references.pmid: 15665051
references.citation: Science. 2004 Oct 8;306(5694):271-5
references.pmid: 15358865
references.citation: EMBO J. 2007 Jan 10;26(1):113-22
references.pmid: 17170702
references.citation: Science. 2003 Dec 12;302(5652):1972-5
references.pmid: 14671306
references.citation: Science. 1997 Aug 1;277(5326):693-6
references.pmid: 9235893
references.citation: Am J Physiol Heart Circ Physiol. 2001 Sep;281(3):H1223-32
references.pmid: 11514291
references.citation: Mol Cell. 2000 Sep;6(3):539-50
references.pmid: 11030334
references.citation: J Biol Chem. 2011 Mar 4;286(9):7468-78
references.pmid: 21159781
references.citation: Am J Physiol Heart Circ Physiol. 2006 Jun;290(6):H2204-9
references.pmid: 16415070
references.citation: FEBS Lett. 1997 Dec 22;420(1):25-7
references.pmid: 9450543
references.citation: Bioessays. 2002 Oct;24(10):881-4
references.pmid: 12325120
references.citation: J Biol Chem. 2004 Aug 27;279(35):36440-4
references.pmid: 15247280
references.citation: J Card Fail. 2008 Apr;14(3):245-53
references.pmid: 18381189
references.citation: EMBO Rep. 2008 Jun;9(6):536-42
references.pmid: 18516089
references.citation: Circ Res. 2008 Jan 4;102(1):16-31
references.pmid: 18174472
references.citation: Mol Cell. 2003 Mar;11(3):695-707
references.pmid: 12667452
references.citation: J Steroid Biochem Mol Biol. 2003 Nov;87(2-3):207-21
references.pmid: 14672741
references.citation: Nat Genet. 2007 Oct;39(10):1225-34
references.pmid: 17767158
references.citation: Hear Res. 1991 Aug;54(2):164-208
references.pmid: 1938625
references.citation: Curr Heart Fail Rep. 2004 Apr-May;1(1):5-8
references.pmid: 16036018
references.citation: Nature. 2006 Jun 1;441(7093):646-50
references.pmid: 16511445
references.citation: Wiley Interdiscip Rev Syst Biol Med. 2011 Jul-Aug;3(4):446-57
references.pmid: 21197655
references.citation: Circ Res. 1998 Aug 24;83(4):345-52
references.pmid: 9721691
references.citation: FASEB J. 2003 Apr;17(6):749-51
references.pmid: 12594183
references.citation: Am J Physiol Heart Circ Physiol. 2005 Nov;289(5):H2039-47
references.pmid: 15994857
references.citation: Cardiovasc Res. 2011 Jan 1;89(1):119-28
references.pmid: 20724307
references.citation: J Endocrinol. 2008 Jun;197(3):493-501
references.pmid: 18492815
references.citation: Oncogene. 2007 May 14;26(22):3122-42
references.pmid: 17496911
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):8985-90
references.pmid: 10908671
references.citation: Endocrinology. 2003 Aug;144(8):3469-76
references.pmid: 12865327
references.citation: Physiol Genomics. 2003 Aug 15;14(3):251-60
references.pmid: 12824457
references.citation: J Biol Chem. 2007 Feb 2;282(5):3273-81
references.pmid: 17121812
references.citation: Surgery. 2009 Aug;146(2):145-54
references.pmid: 19628068
references.citation: Endocrinology. 1997 Nov;138(11):4613-21
references.pmid: 9348186
references.citation: Annu Rev Physiol. 2010;72:81-94
references.pmid: 20148668
references.citation: Nat Cell Biol. 2006 Oct;8(10):1064-73
references.pmid: 16964248
references.citation: J Biol Chem. 2009 Jul 24;284(30):20090-8
references.pmid: 19483080
references.citation: Mol Cell Biol. 2007 Jan;27(2):510-7
references.pmid: 17101801
references.citation: Am J Physiol Heart Circ Physiol. 2005 Feb;288(2):H469-76
references.pmid: 15374829
references.citation: Trends Genet. 1999 Mar;15(3):98-103
references.pmid: 10203806
references.citation: Sci STKE. 2005 Apr 26;2005(281):re5
references.pmid: 15855411
references.citation: Circ Res. 2009 Aug 14;105(4):343-52
references.pmid: 19608983
references.citation: Am J Pathol. 2011 Mar;178(3):1043-58
references.pmid: 21356357
references.citation: Circulation. 2006 Sep 19;114(12):1269-76
references.pmid: 16952980
references.citation: Am J Physiol Regul Integr Comp Physiol. 2009 Apr;296(4):R972-8
references.pmid: 19211725
references.citation: Nature. 2009 Mar 26;458(7237):438-44
references.pmid: 19325623
references.citation: Mol Cell. 2002 May;9(5):945-56
references.pmid: 12049732
references.citation: Mol Cell Biol. 2005 Jul;25(13):5389-95
references.pmid: 15964796
references.citation: Mol Endocrinol. 1998 Jun;12(6):842-54
references.pmid: 9626660
references.citation: J Cell Physiol. 2011 Oct;226(10):2543-54
references.pmid: 21792911
references.citation: Surgery. 2008 Aug;144(2):233-8
references.pmid: 18656630
references.citation: Nature. 2009 Mar 26;458(7237):445-52
references.pmid: 19325624
references.citation: Mol Endocrinol. 2003 Feb;17(2):203-8
references.pmid: 12554748
references.citation: Science. 2003 Apr 11;300(5617):342-4
references.pmid: 12690203
references.citation: Circulation. 2001 Sep 18;104(12):1419-23
references.pmid: 11560859
references.citation: Acta Physiol (Oxf). 2007 Jan;189(1):23-31
references.pmid: 17280554
references.citation: Physiol Genomics. 2011 Apr 27;43(8):438-46
references.pmid: 21325064
references.citation: Mol Cell Biol. 2001 Dec;21(24):8521-32
references.pmid: 11713287
references.citation: EMBO J. 2003 Oct 15;22(20):5446-58
references.pmid: 14532117
references.citation: Nature. 2002 Aug 8;418(6898):636-41
references.pmid: 12167861
references.citation: Cancer Cell. 2009 Apr 7;15(4):245-7
references.pmid: 19345321
references.citation: Biochem Soc Trans. 2007 Dec;35(Pt 6):1414-8
references.pmid: 18031234
references.citation: Nature. 1997 May 15;387(6630):299-303
references.pmid: 9153396
references.citation: Curr Biol. 1997 Apr 1;7(4):261-9
references.pmid: 9094314
references.citation: Circ Res. 2009 Jan 30;104(2):265-75, 11p following 275
references.pmid: 19074476
references.citation: EMBO J. 2004 Dec 8;23(24):4813-23
references.pmid: 15538384
references.citation: Cell. 1998 Apr 17;93(2):215-28
references.pmid: 9568714
references.citation: Chem Res Toxicol. 2004 May;17(5):679-84
references.pmid: 15144225
references.citation: J Biol Chem. 2003 Apr 4;278(14):12361-6
references.pmid: 12517744
references.citation: Nat Genet. 1998 Feb;18(2):143-6
references.pmid: 9462742
references.citation: Proc Natl Acad Sci U S A. 1979 Dec;76(12):6270-3
references.pmid: 293720
references.citation: Mol Endocrinol. 2005 Dec;19(12):2901-14
references.pmid: 16037132
references.citation: Mol Cell Biol. 1999 Jun;19(6):4535-45
references.pmid: 10330192
references.citation: Circ Res. 2011 Sep 2;109(6):687-96
references.pmid: 21885836
references.citation: Am J Physiol Heart Circ Physiol. 2000 Nov;279(5):H2277-84
references.pmid: 11045963
references.citation: Cardiovasc Res. 2008 Aug 1;79(3):472-80
references.pmid: 18375498
references.citation: Mol Cell Biol. 2001 Jul;21(13):4404-12
references.pmid: 11390668
references.citation: Diabetes. 2001 Oct;50(10):2363-75
references.pmid: 11574421
references.citation: Cardiovasc Res. 2009 Sep 1;83(4):605-10
references.pmid: 19541668
references.citation: J Biol Chem. 2002 Oct 4;277(40):37254-9
references.pmid: 12118000
references.citation: Nat Cell Biol. 2008 Feb;10(2):138-48
references.pmid: 18204439
references.citation: Cell Stress Chaperones. 2003 Winter;8(4):303-8
references.pmid: 15115282
references.citation: Cancer Cell. 2006 Dec;10(6):501-14
references.pmid: 17157790
references.citation: J Cell Biol. 2002 Mar 4;156(5):817-28
references.pmid: 11864996
references.citation: J Biol Chem. 2000 May 5;275(18):13321-9
references.pmid: 10788439
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1649-54
references.pmid: 15668399
references.citation: Biochem Soc Symp. 2006;(73):121-9
references.pmid: 16626293
references.citation: Nature. 2002 Apr 11;416(6881):648-53
references.pmid: 11923872
references.citation: Science. 2005 Feb 18;307(5712):1098-101
references.pmid: 15718470
references.citation: Cell. 2000 Dec 8;103(6):843-52
references.pmid: 11136970
references.citation: Mol Pharmacol. 2001 Apr;59(4):867-74
references.pmid: 11259632
references.citation: J Biol Chem. 1997 Nov 28;272(48):30491-7
references.pmid: 9374542
references.citation: J Clin Invest. 2007 Nov;117(11):3211-23
references.pmid: 17965779
references.citation: Nature. 2009 Mar 26;458(7237):430-7
references.pmid: 19325622
references.citation: Science. 1998 Dec 11;282(5396):2092-5
references.pmid: 9851932
references.citation: Trends Cell Biol. 1999 Mar;9(3):107-12
references.pmid: 10201076
references.citation: Circ Res. 1997 Mar;80(3):336-44
references.pmid: 9048653
references.citation: Clin Endocrinol (Oxf). 2008 Sep;69(3):347-58
references.pmid: 18462260
references.citation: Arteriosclerosis. 1990 Nov-Dec;10(6):1051-7
references.pmid: 2244855
references.citation: J Biol Chem. 2009 Oct 2;284(40):27195-210
references.pmid: 19638633
references.citation: Circ Res. 2010 Jun 11;106(11):1692-702
references.pmid: 20413784