title: Ubiquitin C-terminal hydrolase L1 (UCH-L1) acts as a novel potentiator of cyclin-dependent kinases to enhance cell proliferation independently of its hydrolase activity.
abstract: Dysregulation of cell proliferation and the cell cycle are associated with various diseases, such as cancer. Cyclin-dependent kinases (CDKs) play central roles in cell proliferation and the cell cycle. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed in a restricted range of tissues, including the brain and numerous types of cancer. However, the molecular functions of UCH-L1 remain elusive. In this study, we found that UCH-L1 physically interacts with CDK1, CDK4, and CDK5, enhancing their kinase activity. Using several mutants of UCH-L1, we showed that this enhancement is dependent upon interaction levels between UCH-L1 and CDKs but is independent of the known ubiquitin-related functions of UCH-L1. Gain- and loss-of-function studies revealed that UCH-L1 enhances proliferation of multiple cell types, including human cancer cells. Inhibition of the interaction between UCH-L1 and cell cycle-associated CDK resulted in the abolishment of UCH-L1-induced enhancement of cell proliferation. RNA interference of UCH-L1 reduced the growth of human xenograft tumors in mice. We concluded that UCH-L1 is a novel regulator of the kinase activities of CDKs. We believe that our findings from this study will significantly contribute to our understanding of cell cycle-associated diseases.
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. kabuta@ncnp.go.jp
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kabuta
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mitsui
authors.forename: Masaki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Chihana
authors.initials: C
authors.lastname: Kabuta
authors.forename: Chiho
authors.initials: C
authors.lastname: Konya
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Tsuchiya
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hatanaka
authors.forename: Kenko
authors.initials: K
authors.lastname: Uchida
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Hohjoh
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014183:Transplantation, Heterologous; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: D016203:CDC2 Protein Kinase; D051358:Cyclin-Dependent Kinase 4; D051360:Cyclin-Dependent Kinase 5; D009363:Neoplasm Proteins; D043222:Ubiquitin Thiolesterase; C482860:UCHL1 protein, human; C495900:CDK4 protein, human; C495905:CDK5 protein, human; C495902:Cdk4 protein, mouse; C495906:Cdk5 protein, mouse; C496976:Uchl1 protein, mouse
keywords: Cancer; Cell Growth; Cell Proliferation; Cyclin-dependent Kinase (CDK); Protein Complexes; Protein-Protein Interactions; Tumor Marker; UCH-L1
references.citation: Cell Growth Differ. 1995 Feb;6(2):211-7
references.pmid: 7756180
references.citation: Hepatogastroenterology. 2003 Sep-Oct;50(53):1278-80
references.pmid: 14571718
references.citation: J Neurochem. 1996 Jan;66(1):35-46
references.pmid: 8522974
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13650-5
references.pmid: 14595022
references.citation: J Neurosci. 1998 Apr 15;18(8):2801-7
references.pmid: 9525997
references.citation: J Neurochem. 2010 Oct;115(2):423-37
references.pmid: 20670374
references.citation: Clin Cancer Res. 2000 Dec;6(12):4764-7
references.pmid: 11156232
references.citation: J Neuropathol Exp Neurol. 2002 Aug;61(8):678-88
references.pmid: 12152783
references.citation: Nature. 1998 Oct 1;395(6701):451-2
references.pmid: 9774100
references.citation: Science. 1994 Dec 16;266(5192):1821-8
references.pmid: 7997877
references.citation: J Biol Chem. 2002 Mar 1;277(9):6846-51
references.pmid: 11724774
references.citation: Nature. 1995 Jul 27;376(6538):313-20
references.pmid: 7630397
references.citation: Br J Haematol. 2004 Nov;127(3):292-8
references.pmid: 15491288
references.citation: Autophagy. 2008 Aug;4(6):827-9
references.pmid: 18635949
references.citation: Acta Neuropathol. 1997 Mar;93(3):294-300
references.pmid: 9083562
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3585-90
references.pmid: 17360686
references.citation: Nat Cell Biol. 2006 Jan;8(1):17-26
references.pmid: 16341208
references.citation: Biochemistry. 1998 Mar 10;37(10):3358-68
references.pmid: 9521656
references.citation: Hum Mol Genet. 2003 Aug 15;12(16):1945-58
references.pmid: 12913066
references.citation: Autophagy. 2013 Mar;9(3):403-9
references.pmid: 23291500
references.citation: Neurochem Int. 2010 Dec;57(8):906-13
references.pmid: 20933032
references.citation: Neurochem Int. 2007 Jan;50(1):119-29
references.pmid: 16965839
references.citation: Biochem Biophys Res Commun. 2009 Sep 11;387(1):121-6
references.pmid: 19576169
references.citation: Oncogene. 2002 May 2;21(19):3003-10
references.pmid: 12082530
references.citation: Am J Pathol. 2006 Nov;169(5):1722-9
references.pmid: 17071595
references.citation: Science. 1989 Nov 3;246(4930):670-3
references.pmid: 2530630
references.citation: Cancer Sci. 2006 Jun;97(6):523-9
references.pmid: 16734731
references.citation: Hum Mol Genet. 2008 May 15;17(10):1482-96
references.pmid: 18250096
references.citation: Leukemia. 2010 Sep;24(9):1641-55
references.pmid: 20574456
references.citation: Biochem Biophys Res Commun. 2003 Apr 25;304(1):176-83
references.pmid: 12705903
references.citation: J Biol Chem. 2008 Aug 29;283(35):23731-8
references.pmid: 18550537
references.citation: J Biol Chem. 2006 Oct 13;281(41):30524-33
references.pmid: 16920710
references.citation: Biochem Biophys Res Commun. 2010 Apr 9;394(3):697-702
references.pmid: 20226764
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3489-94
references.pmid: 23359680
references.citation: Exp Anim. 2003 Jan;52(1):1-9
references.pmid: 12638230
references.citation: J Urol. 2008 Jul;180(1):343-51
references.pmid: 18499164
references.citation: Genes Dev. 1996 Apr 1;10(7):816-25
references.pmid: 8846918
references.citation: Biol Reprod. 2004 Aug;71(2):515-21
references.pmid: 15084487
references.citation: Nature. 1995 Mar 9;374(6518):131-4
references.pmid: 7877684
references.citation: J Neurosci. 2003 Apr 1;23(7):2557-63
references.pmid: 12684440
references.citation: FEBS Lett. 1991 Sep 23;290(1-2):131-4
references.pmid: 1833240
references.citation: Oncogene. 2009 Jan 8;28(1):117-27
references.pmid: 18820707
references.citation: Clin Cancer Res. 2002 Jan;8(1):192-5
references.pmid: 11801558
references.citation: Nature. 1994 Sep 29;371(6496):423-6
references.pmid: 8090222
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2253-8
references.pmid: 14982996
references.citation: Neuroreport. 1996 Nov 25;7(18):3047-9
references.pmid: 9116237
references.citation: J Neurosci. 2008 Aug 27;28(35):8747-55
references.pmid: 18753376
references.citation: Cell. 2002 Oct 18;111(2):209-18
references.pmid: 12408865
references.citation: Annu Rev Cell Dev Biol. 1997;13:261-91
references.pmid: 9442875
references.citation: Biochem Biophys Res Commun. 2008 Dec 19;377(3):741-6
references.pmid: 18835249
references.citation: Am J Pathol. 1997 Jun;150(6):1933-9
references.pmid: 9176387
references.citation: Am J Pathol. 1999 Sep;155(3):711-5
references.pmid: 10487828
references.citation: Nat Genet. 1999 May;22(1):44-52
references.pmid: 10319860
references.citation: J Clin Endocrinol Metab. 2009 Feb;94(2):434-41
references.pmid: 19017757
references.citation: Nature. 2007 Aug 16;448(7155):811-5
references.pmid: 17700700
references.citation: EMBO J. 2006 Jun 7;25(11):2358-67
references.pmid: 16710296
references.citation: Int J Cancer. 2006 Sep 15;119(6):1338-44
references.pmid: 16642472