• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of molcellbPermissionsJournals.ASM.orgJournalMCB ArticleJournal InfoAuthorsReviewers
Mol Cell Biol. Sep 1996; 16(9): 4808–4817.
PMCID: PMC231482

The murine DUB-1 gene is specifically induced by the betac subunit of interleukin-3 receptor.


Cytokines regulate cell growth and differentiation by inducing the expression of specific target genes. We have recently isolated a cytokine-inducible, immediate-early cDNA, DUB-1, that encodes a deubiquitinating enzyme. The DUB-1 mRNA was specifically induced by the receptors for interleukin-3, granulocyte-macrophage colony-stimulating factor, and interleukin-5, suggesting a role for the beta common (betac subunit known to be shared by these receptors. In order to identify the mechanism of cytokine induction, we isolated a murine genomic clone for DUB-1 containing a functional promoter region. The DUB-1 gene contains two exons, and the nucleotide sequence of its coding region is identical to the sequence of DUB-1 cDNA. Various regions of the 5' flanking region of the DUB-1 gene were assayed for cytokine-inducible activity. An enhancer region that retains the beta c-specific inducible activity of the DUB-1 gene was identified. Enhancer activity was localized to a 112-bp fragment located 1.4 kb upstream from the ATG start codon. Gel mobility shift assays revealed two specific protein complexes that bound to this minimal enhancer region. One complex was induced by betac signaling, while the other was noninducible. Finally, the membrane-proximal region of human betac was required for DUB-1 induction. In conclusion, DUB-1 is the first example of an immediate-early gene that is induced by a specific subunit of a cytokine receptor. Further analysis of the DUB-1 enhancer element may reveal specific determinants of a betac-specific signaling pathway.

Full Text

The Full Text of this article is available as a PDF (1.7M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Andrews NC, Faller DV. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res. 1991 May 11;19(9):2499–2499. [PMC free article] [PubMed]
  • Azam M, Erdjument-Bromage H, Kreider BL, Xia M, Quelle F, Basu R, Saris C, Tempst P, Ihle JN, Schindler C. Interleukin-3 signals through multiple isoforms of Stat5. EMBO J. 1995 Apr 3;14(7):1402–1411. [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]
  • Beadling C, Johnson KW, Smith KA. Isolation of interleukin 2-induced immediate-early genes. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2719–2723. [PMC free article] [PubMed]
  • Brizzi MF, Zini MG, Aronica MG, Blechman JM, Yarden Y, Pegoraro L. Convergence of signaling by interleukin-3, granulocyte-macrophage colony-stimulating factor, and mast cell growth factor on JAK2 tyrosine kinase. J Biol Chem. 1994 Dec 16;269(50):31680–31684. [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]
  • Cochran BH. Regulation of immediate early gene expression. NIDA Res Monogr. 1993;125:3–24. [PubMed]
  • D'Andrea AD, Lodish HF, Wong GG. Expression cloning of the murine erythropoietin receptor. Cell. 1989 Apr 21;57(2):277–285. [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]
  • Darnell JE, Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. [PubMed]
  • Devos R, Plaetinck G, Van der Heyden J, Cornelis S, Vandekerckhove J, Fiers W, Tavernier J. Molecular basis of a high affinity murine interleukin-5 receptor. EMBO J. 1991 Aug;10(8):2133–2137. [PMC free article] [PubMed]
  • Gearing DP, King JA, Gough NM, Nicola NA. Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor. EMBO J. 1989 Dec 1;8(12):3667–3676. [PMC free article] [PubMed]
  • Génin P, Bragança J, Darracq N, Doly J, Civas A. A novel PRD I and TG binding activity involved in virus-induced transcription of IFN-A genes. Nucleic Acids Res. 1995 Dec 25;23(24):5055–5063. [PMC free article] [PubMed]
  • Gouilleux F, Pallard C, Dusanter-Fourt I, Wakao H, Haldosen LA, Norstedt G, Levy D, Groner B. Prolactin, growth hormone, erythropoietin and granulocyte-macrophage colony stimulating factor induce MGF-Stat5 DNA binding activity. EMBO J. 1995 May 1;14(9):2005–2013. [PMC free article] [PubMed]
  • Hayashida K, Kitamura T, Gorman DM, Arai K, Yokota T, Miyajima A. Molecular cloning of a second subunit of the receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF): reconstitution of a high-affinity GM-CSF receptor. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9655–9659. [PMC free article] [PubMed]
  • Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL. An interleukin-4-induced transcription factor: IL-4 Stat. Science. 1994 Sep 16;265(5179):1701–1706. [PubMed]
  • Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Thierfelder WE, Kreider B, Silvennoinen O. Signaling by the cytokine receptor superfamily: JAKs and STATs. Trends Biochem Sci. 1994 May;19(5):222–227. [PubMed]
  • Itoh N, Yonehara S, Schreurs J, Gorman DM, Maruyama K, Ishii A, Yahara I, Arai K, Miyajima A. Cloning of an interleukin-3 receptor gene: a member of a distinct receptor gene family. Science. 1990 Jan 19;247(4940):324–327. [PubMed]
  • Kawamura M, McVicar DW, Johnston JA, Blake TB, Chen YQ, Lal BK, Lloyd AR, Kelvin DJ, Staples JE, Ortaldo JR, et al. Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6374–6378. [PMC free article] [PubMed]
  • Kitamura T, Hayashida K, Sakamaki K, Yokota T, Arai K, Miyajima A. Reconstitution of functional receptors for human granulocyte/macrophage colony-stimulating factor (GM-CSF): evidence that the protein encoded by the AIC2B cDNA is a subunit of the murine GM-CSF receptor. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5082–5086. [PMC free article] [PubMed]
  • 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]
  • 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]
  • 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]
  • 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]
  • Mui AL, Wakao H, O'Farrell AM, Harada N, Miyajima A. Interleukin-3, granulocyte-macrophage colony stimulating factor and interleukin-5 transduce signals through two STAT5 homologs. EMBO J. 1995 Mar 15;14(6):1166–1175. [PMC free article] [PubMed]
  • Nicola NA, Metcalf D. Subunit promiscuity among hemopoietic growth factor receptors. Cell. 1991 Oct 4;67(1):1–4. [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]
  • Papas TS, Fisher RJ, Bhat N, Fujiwara S, Watson DK, Lautenberger J, Seth A, Chen ZQ, Burdett L, Pribyl L, et al. The ets family of genes: molecular biology and functional implications. Curr Top Microbiol Immunol. 1989;149:143–147. [PubMed]
  • Park LS, Martin U, Sorensen R, Luhr S, Morrissey PJ, Cosman D, Larsen A. Cloning of the low-affinity murine granulocyte-macrophage colony-stimulating factor receptor and reconstitution of a high-affinity receptor complex. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4295–4299. [PMC free article] [PubMed]
  • Quelle FW, Sato N, Witthuhn BA, Inhorn RC, Eder M, Miyajima A, Griffin JD, Ihle JN. JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region. Mol Cell Biol. 1994 Jul;14(7):4335–4341. [PMC free article] [PubMed]
  • Quelle FW, Shimoda K, Thierfelder W, Fischer C, Kim A, Ruben SM, Cleveland JL, Pierce JH, Keegan AD, Nelms K, et al. Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis. Mol Cell Biol. 1995 Jun;15(6):3336–3343. [PMC free article] [PubMed]
  • Robertson LM, Kerppola TK, Vendrell M, Luk D, Smeyne RJ, Bocchiaro C, Morgan JI, Curran T. Regulation of c-fos expression in transgenic mice requires multiple interdependent transcription control elements. Neuron. 1995 Feb;14(2):241–252. [PubMed]
  • Satake M, Nomura S, Yamaguchi-Iwai Y, Takahama Y, Hashimoto Y, Niki M, Kitamura Y, Ito Y. Expression of the Runt domain-encoding PEBP2 alpha genes in T cells during thymic development. Mol Cell Biol. 1995 Mar;15(3):1662–1670. [PMC free article] [PubMed]
  • Sato N, Miyajima A. Multimeric cytokine receptors: common versus specific functions. Curr Opin Cell Biol. 1994 Apr;6(2):174–179. [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]
  • Seidel HM, Milocco LH, Lamb P, Darnell JE, Jr, Stein RB, Rosen J. Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):3041–3045. [PMC free article] [PubMed]
  • Seldin DC, Leder P. Mutational analysis of a critical signaling domain of the human interleukin 4 receptor. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2140–2144. [PMC free article] [PubMed]
  • Sims SH, Cha Y, Romine MF, Gao PQ, Gottlieb K, Deisseroth AB. A novel interferon-inducible domain: structural and functional analysis of the human interferon regulatory factor 1 gene promoter. Mol Cell Biol. 1993 Jan;13(1):690–702. [PMC free article] [PubMed]
  • Takaki S, Kanazawa H, Shiiba M, Takatsu K. A critical cytoplasmic domain of the interleukin-5 (IL-5) receptor alpha chain and its function in IL-5-mediated growth signal transduction. Mol Cell Biol. 1994 Nov;14(11):7404–7413. [PMC free article] [PubMed]
  • Takaki S, Mita S, Kitamura T, Yonehara S, Yamaguchi N, Tominaga A, Miyajima A, Takatsu K. Identification of the second subunit of the murine interleukin-5 receptor: interleukin-3 receptor-like protein, AIC2B is a component of the high affinity interleukin-5 receptor. EMBO J. 1991 Oct;10(10):2833–2838. [PMC free article] [PubMed]
  • Takaki S, Tominaga A, Hitoshi Y, Mita S, Sonoda E, Yamaguchi N, Takatsu K. Molecular cloning and expression of the murine interleukin-5 receptor. EMBO J. 1990 Dec;9(13):4367–4374. [PMC free article] [PubMed]
  • Tsai SF, Martin DI, Zon LI, D'Andrea AD, Wong GG, Orkin SH. Cloning of cDNA for the major DNA-binding protein of the erythroid lineage through expression in mammalian cells. Nature. 1989 Jun 8;339(6224):446–451. [PubMed]
  • Wakao H, Harada N, Kitamura T, Mui AL, Miyajima A. Interleukin 2 and erythropoietin activate STAT5/MGF via distinct pathways. EMBO J. 1995 Jun 1;14(11):2527–2535. [PMC free article] [PubMed]
  • Watanabe S, Ishida S, Koike K, Arai K. Characterization of cis-regulatory elements of the c-myc promoter responding to human GM-CSF or mouse interleukin 3 in mouse proB cell line BA/F3 cells expressing the human GM-CSF receptor. Mol Biol Cell. 1995 Jun;6(6):627–636. [PMC free article] [PubMed]
  • Watanabe S, Muto A, Yokota T, Miyajima A, Arai K. Differential regulation of early response genes and cell proliferation through the human granulocyte macrophage colony-stimulating factor receptor: selective activation of the c-fos promoter by genistein. Mol Biol Cell. 1993 Oct;4(10):983–992. [PMC free article] [PubMed]
  • Watson DK, McWilliams MJ, Lapis P, Lautenberger JA, Schweinfest CW, Papas TS. Mammalian ets-1 and ets-2 genes encode highly conserved proteins. Proc Natl Acad Sci U S A. 1988 Nov;85(21):7862–7866. [PMC free article] [PubMed]
  • Wegenka UM, Buschmann J, Lütticken C, Heinrich PC, Horn F. Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level. Mol Cell Biol. 1993 Jan;13(1):276–288. [PMC free article] [PubMed]
  • Weinstein Y, Morishita K, Cleveland JL, Ihle JN. Interleukin 3 (IL-3) induces transcription from nonrearranged T cell receptor gamma loci in IL-3-dependent cell lines. J Exp Med. 1989 Jun 1;169(6):2059–2071. [PMC free article] [PubMed]
  • Witthuhn BA, Quelle FW, Silvennoinen O, Yi T, Tang B, Miura O, Ihle JN. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell. 1993 Jul 30;74(2):227–236. [PubMed]
  • Witthuhn BA, Silvennoinen O, Miura O, Lai KS, Cwik C, Liu ET, Ihle JN. Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature. 1994 Jul 14;370(6485):153–157. [PubMed]
  • Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, Hara T, Miyajima A. A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J. 1995 Jun 15;14(12):2816–2826. [PMC free article] [PubMed]
  • Zhu Y, Carroll M, Papa FR, Hochstrasser M, D'Andrea AD. DUB-1, a deubiquitinating enzyme with growth-suppressing activity. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3275–3279. [PMC free article] [PubMed]
  • Zon LI, Moreau JF, Koo JW, Mathey-Prevot B, D'Andrea AD. The erythropoietin receptor transmembrane region is necessary for activation by the Friend spleen focus-forming virus gp55 glycoprotein. Mol Cell Biol. 1992 Jul;12(7):2949–2957. [PMC free article] [PubMed]

Articles from Molecular and Cellular Biology are provided here courtesy of American Society for Microbiology (ASM)


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...