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Proc Natl Acad Sci U S A. Apr 16, 1996; 93(8): 3275–3279.
PMCID: PMC39596

DUB-1, a deubiquitinating enzyme with growth-suppressing activity.

Abstract

Cytokines regulate cell growth by inducing the expression of specific target genes. Using the differential display method, we have cloned a cytokine-inducible immediate early gene, DUB-1 (for deubiquitinating enzyme). DUB-1 is related to members of the UBP superfamily of deubiquitinating enzymes, which includes the oncoprotein Tre-2. A glutathione S-transferase-DUB-1 fusion protein cleaved ubiquitin from a ubiquitin-beta-galactosidase protein. When a conserved cysteine residue of DUB-1, required for ubiquitin-specific thiol protease activity, was mutated to serine (C60S), deubiquitinating activity was abolished. Continuous expression of DUB-1 from a steroid-inducible promoter induced growth arrest in the G1 phase of the cell cycle. Cells arrested by DUB-1 expression remained viable and resumed proliferation upon steroid withdrawal. Our results suggest that DUB-1 regulates cellular growth by modulating either the ubiquitin-dependent proteolysis or the ubiquitination state of an unknown growth regulatory factor(s).

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  • Kitamura T, Sato N, Arai K, Miyajima A. Expression cloning of the human IL-3 receptor cDNA reveals a shared beta subunit for the human IL-3 and GM-CSF receptors. Cell. 1991 Sep 20;66(6):1165–1174. [PubMed]
  • Sato N, Sakamaki K, Terada N, Arai K, Miyajima A. Signal transduction by the high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common beta subunit responsible for different signaling. EMBO J. 1993 Nov;12(11):4181–4189. [PMC free article] [PubMed]
  • Murray A. Cyclin ubiquitination: the destructive end of mitosis. Cell. 1995 Apr 21;81(2):149–152. [PubMed]
  • Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995 May 15;9(10):1149–1163. [PubMed]
  • Hershko A. Ubiquitin-mediated protein degradation. J Biol Chem. 1988 Oct 25;263(30):15237–15240. [PubMed]
  • Hershko A, Ciechanover A. The ubiquitin system for protein degradation. Annu Rev Biochem. 1992;61:761–807. [PubMed]
  • Finley D, Chau V. Ubiquitination. Annu Rev Cell Biol. 1991;7:25–69. [PubMed]
  • Ciechanover A. The ubiquitin-proteasome proteolytic pathway. Cell. 1994 Oct 7;79(1):13–21. [PubMed]
  • Peters JM, Cejka Z, Harris JR, Kleinschmidt JA, Baumeister W. Structural features of the 26 S proteasome complex. J Mol Biol. 1993 Dec 20;234(4):932–937. [PubMed]
  • Peters JM. Proteasomes: protein degradation machines of the cell. Trends Biochem Sci. 1994 Sep;19(9):377–382. [PubMed]
  • Glotzer M, Murray AW, Kirschner MW. Cyclin is degraded by the ubiquitin pathway. Nature. 1991 Jan 10;349(6305):132–138. [PubMed]
  • Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF, Rolfe M. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science. 1995 Aug 4;269(5224):682–685. [PubMed]
  • Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell. 1993 Nov 5;75(3):495–505. [PubMed]
  • Chowdary DR, Dermody JJ, Jha KK, Ozer HL. Accumulation of p53 in a mutant cell line defective in the ubiquitin pathway. Mol Cell Biol. 1994 Mar;14(3):1997–2003. [PMC free article] [PubMed]
  • Treier M, Staszewski LM, Bohmann D. Ubiquitin-dependent c-Jun degradation in vivo is mediated by the delta domain. Cell. 1994 Sep 9;78(5):787–798. [PubMed]
  • Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, Ballard D, Maniatis T. Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev. 1995 Jul 1;9(13):1586–1597. [PubMed]
  • Hochstrasser M. Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr Opin Cell Biol. 1995 Apr;7(2):215–223. [PubMed]
  • King RW, Peters JM, Tugendreich S, Rolfe M, Hieter P, Kirschner MW. A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B. Cell. 1995 Apr 21;81(2):279–288. [PubMed]
  • Tugendreich S, Tomkiel J, Earnshaw W, Hieter P. CDC27Hs colocalizes with CDC16Hs to the centrosome and mitotic spindle and is essential for the metaphase to anaphase transition. Cell. 1995 Apr 21;81(2):261–268. [PubMed]
  • Papa FR, Hochstrasser M. The yeast DOA4 gene encodes a deubiquitinating enzyme related to a product of the human tre-2 oncogene. Nature. 1993 Nov 25;366(6453):313–319. [PubMed]
  • Liang P, Pardee AB. Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science. 1992 Aug 14;257(5072):967–971. [PubMed]
  • Liang P, Averboukh L, Pardee AB. Distribution and cloning of eukaryotic mRNAs by means of differential display: refinements and optimization. Nucleic Acids Res. 1993 Jul 11;21(14):3269–3275. [PMC free article] [PubMed]
  • Palacios R, Steinmetz M. Il-3-dependent mouse clones that express B-220 surface antigen, contain Ig genes in germ-line configuration, and generate B lymphocytes in vivo. Cell. 1985 Jul;41(3):727–734. [PubMed]
  • D'Andrea AD, Yoshimura A, Youssoufian H, Zon LI, Koo JW, Lodish HF. The cytoplasmic region of the erythropoietin receptor contains nonoverlapping positive and negative growth-regulatory domains. Mol Cell Biol. 1991 Apr;11(4):1980–1987. [PMC free article] [PubMed]
  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. [PubMed]
  • Feinberg AP, Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. [PubMed]
  • Yamashita T, Barber DL, Zhu Y, Wu N, D'Andrea AD. The Fanconi anemia polypeptide FACC is localized to the cytoplasm. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6712–6716. [PMC free article] [PubMed]
  • Barber DL, D'Andrea AD. Erythropoietin and interleukin-2 activate distinct JAK kinase family members. Mol Cell Biol. 1994 Oct;14(10):6506–6514. [PMC free article] [PubMed]
  • Carroll M, Zhu Y, D'Andrea AD. Erythropoietin-induced cellular differentiation requires prolongation of the G1 phase of the cell cycle. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2869–2873. [PMC free article] [PubMed]
  • Liboi E, Carroll M, D'Andrea AD, Mathey-Prevot B. Erythropoietin receptor signals both proliferation and erythroid-specific differentiation. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11351–11355. [PMC free article] [PubMed]
  • Shaw G, Kamen R. A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986 Aug 29;46(5):659–667. [PubMed]
  • Nakamura T, Hillova J, Mariage-Samson R, Onno M, Huebner K, Cannizzaro LA, Boghosian-Sell L, Croce CM, Hill M. A novel transcriptional unit of the tre oncogene widely expressed in human cancer cells. Oncogene. 1992 Apr;7(4):733–741. [PubMed]
  • Gupta K, Copeland NG, Gilbert DJ, Jenkins NA, Gray DA. Unp, a mouse gene related to the tre oncogene. Oncogene. 1993 Aug;8(8):2307–2310. [PubMed]
  • Dang CV, Lee WM. Identification of the human c-myc protein nuclear translocation signal. Mol Cell Biol. 1988 Oct;8(10):4048–4054. [PMC free article] [PubMed]
  • Onno M, Nakamura T, Mariage-Samson R, Hillova J, Hill M. Human TRE17 oncogene is generated from a family of homologous polymorphic sequences by single-base changes. DNA Cell Biol. 1993 Mar;12(2):107–118. [PubMed]
  • Tobias JW, Shrader TE, Rocap G, Varshavsky A. The N-end rule in bacteria. Science. 1991 Nov 29;254(5036):1374–1377. [PubMed]
  • Matsushime H, Roussel MF, Ashmun RA, Sherr CJ. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell. 1991 May 17;65(4):701–713. [PubMed]
  • Baker RT, Tobias JW, Varshavsky A. Ubiquitin-specific proteases of Saccharomyces cerevisiae. Cloning of UBP2 and UBP3, and functional analysis of the UBP gene family. J Biol Chem. 1992 Nov 15;267(32):23364–23375. [PubMed]
  • Paolini R, Kinet JP. Cell surface control of the multiubiquitination and deubiquitination of high-affinity immunoglobulin E receptors. EMBO J. 1993 Feb;12(2):779–786. [PMC free article] [PubMed]
  • Corsi D, Galluzzi L, Crinelli R, Magnani M. Ubiquitin is conjugated to the cytoskeletal protein alpha-spectrin in mature erythrocytes. J Biol Chem. 1995 Apr 14;270(15):8928–8935. [PubMed]
  • Sun H, Charles CH, Lau LF, Tonks NK. MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell. 1993 Nov 5;75(3):487–493. [PubMed]
  • Ward Y, Gupta S, Jensen P, Wartmann M, Davis RJ, Kelly K. Control of MAP kinase activation by the mitogen-induced threonine/tyrosine phosphatase PAC1. Nature. 1994 Feb 17;367(6464):651–654. [PubMed]
  • Michieli P, Chedid M, Lin D, Pierce JH, Mercer WE, Givol D. Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res. 1994 Jul 1;54(13):3391–3395. [PubMed]

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