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. 1996 Sep;16(9):4808–4817. doi: 10.1128/mcb.16.9.4808

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

Y Zhu 1, M Pless 1, R Inhorn 1, B Mathey-Prevot 1, A D D'Andrea 1
PMCID: PMC231482  PMID: 8756639

Abstract

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.

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Selected References

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  1. Andrews N. C., Faller D. V. 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. doi: 10.1093/nar/19.9.2499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Azam M., Erdjument-Bromage H., Kreider B. L., Xia M., Quelle F., Basu R., Saris C., Tempst P., Ihle J. N., Schindler C. Interleukin-3 signals through multiple isoforms of Stat5. EMBO J. 1995 Apr 3;14(7):1402–1411. doi: 10.1002/j.1460-2075.1995.tb07126.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barber D. L., D'Andrea A. D. Erythropoietin and interleukin-2 activate distinct JAK kinase family members. Mol Cell Biol. 1994 Oct;14(10):6506–6514. doi: 10.1128/mcb.14.10.6506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beadling C., Johnson K. W., Smith K. A. Isolation of interleukin 2-induced immediate-early genes. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2719–2723. doi: 10.1073/pnas.90.7.2719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brizzi M. F., Zini M. G., Aronica M. G., Blechman J. M., 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] [Google Scholar]
  6. Carroll M., Zhu Y., D'Andrea A. D. 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. doi: 10.1073/pnas.92.7.2869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cochran B. H. Regulation of immediate early gene expression. NIDA Res Monogr. 1993;125:3–24. [PubMed] [Google Scholar]
  8. D'Andrea A. D., Lodish H. F., Wong G. G. Expression cloning of the murine erythropoietin receptor. Cell. 1989 Apr 21;57(2):277–285. doi: 10.1016/0092-8674(89)90965-3. [DOI] [PubMed] [Google Scholar]
  9. D'Andrea A. D., Yoshimura A., Youssoufian H., Zon L. I., Koo J. W., Lodish H. F. The cytoplasmic region of the erythropoietin receptor contains nonoverlapping positive and negative growth-regulatory domains. Mol Cell Biol. 1991 Apr;11(4):1980–1987. doi: 10.1128/mcb.11.4.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Darnell J. E., Jr, Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. doi: 10.1126/science.8197455. [DOI] [PubMed] [Google Scholar]
  11. 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. doi: 10.1002/j.1460-2075.1991.tb07747.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gearing D. P., King J. A., Gough N. M., Nicola N. A. Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor. EMBO J. 1989 Dec 1;8(12):3667–3676. doi: 10.1002/j.1460-2075.1989.tb08541.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gouilleux F., Pallard C., Dusanter-Fourt I., Wakao H., Haldosen L. A., 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. doi: 10.1002/j.1460-2075.1995.tb07192.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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. doi: 10.1093/nar/23.24.5055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hayashida K., Kitamura T., Gorman D. M., 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. doi: 10.1073/pnas.87.24.9655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hou J., Schindler U., Henzel W. J., Ho T. C., Brasseur M., McKnight S. L. An interleukin-4-induced transcription factor: IL-4 Stat. Science. 1994 Sep 16;265(5179):1701–1706. doi: 10.1126/science.8085155. [DOI] [PubMed] [Google Scholar]
  17. Ihle J. N., Witthuhn B. A., Quelle F. W., Yamamoto K., Thierfelder W. E., Kreider B., Silvennoinen O. Signaling by the cytokine receptor superfamily: JAKs and STATs. Trends Biochem Sci. 1994 May;19(5):222–227. doi: 10.1016/0968-0004(94)90026-4. [DOI] [PubMed] [Google Scholar]
  18. Itoh N., Yonehara S., Schreurs J., Gorman D. M., 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. doi: 10.1126/science.2404337. [DOI] [PubMed] [Google Scholar]
  19. Kawamura M., McVicar D. W., Johnston J. A., Blake T. B., Chen Y. Q., Lal B. K., Lloyd A. R., Kelvin D. J., Staples J. E., Ortaldo J. R. 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. doi: 10.1073/pnas.91.14.6374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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. doi: 10.1073/pnas.88.12.5082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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. doi: 10.1016/0092-8674(91)90039-2. [DOI] [PubMed] [Google Scholar]
  22. Liang P., Averboukh L., Pardee A. B. Distribution and cloning of eukaryotic mRNAs by means of differential display: refinements and optimization. Nucleic Acids Res. 1993 Jul 11;21(14):3269–3275. doi: 10.1093/nar/21.14.3269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Liang P., Pardee A. B. Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science. 1992 Aug 14;257(5072):967–971. doi: 10.1126/science.1354393. [DOI] [PubMed] [Google Scholar]
  24. Liboi E., Carroll M., D'Andrea A. D., 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. doi: 10.1073/pnas.90.23.11351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mui A. L., Wakao H., O'Farrell A. M., 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. doi: 10.1002/j.1460-2075.1995.tb07100.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nicola N. A., Metcalf D. Subunit promiscuity among hemopoietic growth factor receptors. Cell. 1991 Oct 4;67(1):1–4. doi: 10.1016/0092-8674(91)90564-f. [DOI] [PubMed] [Google Scholar]
  27. 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. doi: 10.1016/s0092-8674(85)80053-2. [DOI] [PubMed] [Google Scholar]
  28. Papas T. S., Fisher R. J., Bhat N., Fujiwara S., Watson D. K., Lautenberger J., Seth A., Chen Z. Q., Burdett L., Pribyl L. The ets family of genes: molecular biology and functional implications. Curr Top Microbiol Immunol. 1989;149:143–147. doi: 10.1007/978-3-642-74623-9_13. [DOI] [PubMed] [Google Scholar]
  29. Park L. S., Martin U., Sorensen R., Luhr S., Morrissey P. J., 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. doi: 10.1073/pnas.89.10.4295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Quelle F. W., Sato N., Witthuhn B. A., Inhorn R. C., Eder M., Miyajima A., Griffin J. D., Ihle J. N. 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. doi: 10.1128/mcb.14.7.4335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Quelle F. W., Shimoda K., Thierfelder W., Fischer C., Kim A., Ruben S. M., Cleveland J. L., Pierce J. H., Keegan A. D., Nelms K. 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. doi: 10.1128/mcb.15.6.3336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Robertson L. M., Kerppola T. K., Vendrell M., Luk D., Smeyne R. J., Bocchiaro C., Morgan J. I., Curran T. Regulation of c-fos expression in transgenic mice requires multiple interdependent transcription control elements. Neuron. 1995 Feb;14(2):241–252. doi: 10.1016/0896-6273(95)90282-1. [DOI] [PubMed] [Google Scholar]
  33. 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. doi: 10.1128/mcb.15.3.1662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sato N., Miyajima A. Multimeric cytokine receptors: common versus specific functions. Curr Opin Cell Biol. 1994 Apr;6(2):174–179. doi: 10.1016/0955-0674(94)90133-3. [DOI] [PubMed] [Google Scholar]
  35. 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. doi: 10.1002/j.1460-2075.1993.tb06102.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Seidel H. M., Milocco L. H., Lamb P., Darnell J. E., Jr, Stein R. B., 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. doi: 10.1073/pnas.92.7.3041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Seldin D. C., 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. doi: 10.1073/pnas.91.6.2140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sims S. H., Cha Y., Romine M. F., Gao P. Q., Gottlieb K., Deisseroth A. B. 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. doi: 10.1128/mcb.13.1.690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. 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. doi: 10.1128/mcb.14.11.7404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. 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. doi: 10.1002/j.1460-2075.1991.tb07832.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. 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. doi: 10.1002/j.1460-2075.1990.tb07886.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tsai S. F., Martin D. I., Zon L. I., D'Andrea A. D., Wong G. G., Orkin S. H. 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. doi: 10.1038/339446a0. [DOI] [PubMed] [Google Scholar]
  43. Wakao H., Harada N., Kitamura T., Mui A. L., Miyajima A. Interleukin 2 and erythropoietin activate STAT5/MGF via distinct pathways. EMBO J. 1995 Jun 1;14(11):2527–2535. doi: 10.1002/j.1460-2075.1995.tb07250.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. 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. doi: 10.1091/mbc.6.6.627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. 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. doi: 10.1091/mbc.4.10.983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Watson D. K., McWilliams M. J., Lapis P., Lautenberger J. A., Schweinfest C. W., Papas T. S. Mammalian ets-1 and ets-2 genes encode highly conserved proteins. Proc Natl Acad Sci U S A. 1988 Nov;85(21):7862–7866. doi: 10.1073/pnas.85.21.7862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Wegenka U. M., Buschmann J., Lütticken C., Heinrich P. C., 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. doi: 10.1128/mcb.13.1.276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Weinstein Y., Morishita K., Cleveland J. L., Ihle J. N. 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. doi: 10.1084/jem.169.6.2059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Witthuhn B. A., Quelle F. W., Silvennoinen O., Yi T., Tang B., Miura O., Ihle J. N. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell. 1993 Jul 30;74(2):227–236. doi: 10.1016/0092-8674(93)90414-l. [DOI] [PubMed] [Google Scholar]
  50. Witthuhn B. A., Silvennoinen O., Miura O., Lai K. S., Cwik C., Liu E. T., Ihle J. N. 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. doi: 10.1038/370153a0. [DOI] [PubMed] [Google Scholar]
  51. Yoshimura A., Ohkubo T., Kiguchi T., Jenkins N. A., Gilbert D. J., Copeland N. G., 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. doi: 10.1002/j.1460-2075.1995.tb07281.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Zhu Y., Carroll M., Papa F. R., Hochstrasser M., D'Andrea A. D. DUB-1, a deubiquitinating enzyme with growth-suppressing activity. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3275–3279. doi: 10.1073/pnas.93.8.3275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Zon L. I., Moreau J. F., Koo J. W., Mathey-Prevot B., D'Andrea A. D. 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. doi: 10.1128/mcb.12.7.2949. [DOI] [PMC free article] [PubMed] [Google Scholar]

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