• 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. Apr 1994; 14(4): 2266–2277.
PMCID: PMC358593

A constitutively activated erythropoietin receptor stimulates proliferation and contributes to transformation of multipotent, committed nonerythroid and erythroid progenitor cells.

Abstract

If the env gene of spleen focus-forming virus (SFFV) is replaced by a cDNA encoding a constitutively active form of the erythropoietin receptor, EPO-R(R129C), the resultant recombinant virus, SFFVcEPO-R, induces transient thrombocytosis and erythrocytosis in infected mice. Clonogenic progenitor cell assays of cells from the bone marrow and spleens of these infected mice suggest that EPO-R(R129C) can stimulate proliferation of committed megakaryocytic and erythroid progenitors as well as nonerythroid multipotent progenitors. From the spleens of SFFVcEPO-R-infected mice, eight multiphenotypic immortal cell lines were isolated and characterized. These included primitive erythroid, lymphoid, and monocytic cells. Some expressed proteins characteristic of more than one lineage. All cell lines resulting from SFFVcEPO-R infection contained a mutant form of the p53 gene. However, in contrast to infection by SFFV, activation of PU.1 gene expression, by retroviral integration, was not observed. One cell line had integrated a provirus upstream of the fli-1 gene, in a location typically seen in erythroleukemic cells generated by Friend murine leukemia virus infection. This event led to increased expression of fli-1 in this cell line. Thus, infection by SFFVcEPO-R can induce proliferation and lead to transformation of nonerythroid as well as very immature erythroid progenitor cells. The sites of proviral integration in clonal cell lines are distinct from those in SFFV-derived lines.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.6M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Aihara Y, Bühring HJ, Aihara M, Klein J. An attempt to produce "pre-T" cell hybridomas and to identify their antigens. Eur J Immunol. 1986 Nov;16(11):1391–1399. [PubMed]
  • Aizawa S, Suda Y, Furuta Y, Yagi T, Takeda N, Watanabe N, Nagayoshi M, Ikawa Y. Env-derived gp55 gene of Friend spleen focus-forming virus specifically induces neoplastic proliferation of erythroid progenitor cells. EMBO J. 1990 Jul;9(7):2107–2116. [PMC free article] [PubMed]
  • Auffray C, Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980 Jun;107(2):303–314. [PubMed]
  • Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A. 1990 Sep;87(18):6934–6938. [PMC free article] [PubMed]
  • Behringer RR, Dewey MJ. Cellular site and mode of Fv-2 gene action. Cell. 1985 Feb;40(2):441–447. [PubMed]
  • Ben-David Y, Bernstein A. Friend virus-induced erythroleukemia and the multistage nature of cancer. Cell. 1991 Sep 6;66(5):831–834. [PubMed]
  • Ben-David Y, Giddens EB, Bernstein A. Identification and mapping of a common proviral integration site Fli-1 in erythroleukemia cells induced by Friend murine leukemia virus. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1332–1336. [PMC free article] [PubMed]
  • Ben-David Y, Giddens EB, Letwin K, Bernstein A. Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1. Genes Dev. 1991 Jun;5(6):908–918. [PubMed]
  • Ben David Y, Prideaux VR, Chow V, Benchimol S, Bernstein A. Inactivation of the p53 oncogene by internal deletion or retroviral integration in erythroleukemic cell lines induced by Friend leukemia virus. Oncogene. 1988 Aug;3(2):179–185. [PubMed]
  • Berridge MV, Fraser JK, Carter JM, Lin FK. Effects of recombinant human erythropoietin on megakaryocytes and on platelet production in the rat. Blood. 1988 Sep;72(3):970–977. [PubMed]
  • Burstein SA, Friese P, Downs T, Mei RL. Characteristics of a novel rat anti-mouse platelet monoclonal antibody: application to studies of megakaryocytes. Exp Hematol. 1992 Nov;20(10):1170–1177. [PubMed]
  • Chang JM, Metcalf D, Lang RA, Gonda TJ, Johnson GR. Nonneoplastic hematopoietic myeloproliferative syndrome induced by dysregulated multi-CSF (IL-3) expression. Blood. 1989 May 1;73(6):1487–1497. [PubMed]
  • Cosman D, Lyman SD, Idzerda RL, Beckmann MP, Park LS, Goodwin RG, March CJ. A new cytokine receptor superfamily. Trends Biochem Sci. 1990 Jul;15(7):265–270. [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]
  • Fraser JK, Tan AS, Lin FK, Berridge MV. Expression of specific high-affinity binding sites for erythropoietin on rat and mouse megakaryocytes. Exp Hematol. 1989 Jan;17(1):10–16. [PubMed]
  • Furman WL, Rettenmier CW, Chen JH, Roussel MF, Quinn CO, Sherr CJ. Antibodies to distal carboxyl terminal epitopes in the v-fms-coded glycoprotein do not cross-react with the c-fms gene product. Virology. 1986 Jul 30;152(2):432–445. [PubMed]
  • Goebl MK. The PU.1 transcription factor is the product of the putative oncogene Spi-1. Cell. 1990 Jun 29;61(7):1165–1166. [PubMed]
  • Grau GE, Morrow D, Izui S, Lambert PH. Pathogenesis of the delayed phase of Rauscher virus-induced thrombocytopenia. J Immunol. 1986 Jan;136(2):686–691. [PubMed]
  • Gross-Bellard M, Oudet P, Chambon P. Isolation of high-molecular-weight DNA from mammalian cells. Eur J Biochem. 1973 Jul 2;36(1):32–38. [PubMed]
  • Heard JM, Roussel MF, Rettenmier CW, Sherr CJ. Multilineage hematopoietic disorders induced by transplantation of bone marrow cells expressing the v-fms oncogene. Cell. 1987 Nov 20;51(4):663–673. [PubMed]
  • Heberlein C, Fischer KD, Stoffel M, Nowock J, Ford A, Tessmer U, Stocking C. The gene for erythropoietin receptor is expressed in multipotential hematopoietic and embryonal stem cells: evidence for differentiation stage-specific regulation. Mol Cell Biol. 1992 Apr;12(4):1815–1826. [PMC free article] [PubMed]
  • Hockett RD, de Villartay JP, Pollock K, Poplack DG, Cohen DI, Korsmeyer SJ. Human T-cell antigen receptor (TCR) delta-chain locus and elements responsible for its deletion are within the TCR alpha-chain locus. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9694–9698. [PMC free article] [PubMed]
  • Hromas R, Orazi A, Neiman RS, Maki R, Van Beveran C, Moore J, Klemsz M. Hematopoietic lineage- and stage-restricted expression of the ETS oncogene family member PU.1. Blood. 1993 Nov 15;82(10):2998–3004. [PubMed]
  • Johnson GR, Gonda TJ, Metcalf D, Hariharan IK, Cory S. A lethal myeloproliferative syndrome in mice transplanted with bone marrow cells infected with a retrovirus expressing granulocyte-macrophage colony stimulating factor. EMBO J. 1989 Feb;8(2):441–448. [PMC free article] [PubMed]
  • Keller G, Kennedy M, Papayannopoulou T, Wiles MV. Hematopoietic commitment during embryonic stem cell differentiation in culture. Mol Cell Biol. 1993 Jan;13(1):473–486. [PMC free article] [PubMed]
  • Klemsz MJ, McKercher SR, Celada A, Van Beveren C, Maki RA. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell. 1990 Apr 6;61(1):113–124. [PubMed]
  • Lang RA, Metcalf D, Cuthbertson RA, Lyons I, Stanley E, Kelso A, Kannourakis G, Williamson DJ, Klintworth GK, Gonda TJ, et al. Transgenic mice expressing a hemopoietic growth factor gene (GM-CSF) develop accumulations of macrophages, blindness, and a fatal syndrome of tissue damage. Cell. 1987 Nov 20;51(4):675–686. [PubMed]
  • Lavigueur A, Bernstein A. p53 transgenic mice: accelerated erythroleukemia induction by Friend virus. Oncogene. 1991 Dec;6(12):2197–2201. [PubMed]
  • Leprince D, Gegonne A, Coll J, de Taisne C, Schneeberger A, Lagrou C, Stehelin D. A putative second cell-derived oncogene of the avian leukaemia retrovirus E26. Nature. 1983 Nov 24;306(5941):395–397. [PubMed]
  • Levine AJ, Momand J, Finlay CA. The p53 tumour suppressor gene. Nature. 1991 Jun 6;351(6326):453–456. [PubMed]
  • Li JP, Bestwick RK, Machida C, Kabat D. Role of a membrane glycoprotein in Friend virus erythroleukemia: nucleotide sequences of nonleukemogenic mutant and spontaneous revertant viruses. J Virol. 1986 Feb;57(2):534–538. [PMC free article] [PubMed]
  • Li JP, Bestwick RK, Spiro C, Kabat D. The membrane glycoprotein of Friend spleen focus-forming virus: evidence that the cell surface component is required for pathogenesis and that it binds to a receptor. J Virol. 1987 Sep;61(9):2782–2792. [PMC free article] [PubMed]
  • Li JP, D'Andrea AD, Lodish HF, Baltimore D. Activation of cell growth by binding of Friend spleen focus-forming virus gp55 glycoprotein to the erythropoietin receptor. Nature. 1990 Feb 22;343(6260):762–764. [PubMed]
  • Longmore GD, Lodish HF. An activating mutation in the murine erythropoietin receptor induces erythroleukemia in mice: a cytokine receptor superfamily oncogene. Cell. 1991 Dec 20;67(6):1089–1102. [PubMed]
  • Longmore GD, Pharr P, Neumann D, Lodish HF. Both megakaryocytopoiesis and erythropoiesis are induced in mice infected with a retrovirus expressing an oncogenic erythropoietin receptor. Blood. 1993 Oct 15;82(8):2386–2395. [PubMed]
  • Mager DL, Mak TW, Bernstein A. Quantitative colony method for tumorigenic cells transformed by two distinct strains of Friend leukemia virus. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1703–1707. [PMC free article] [PubMed]
  • Majumdar MK, Cho CL, Fox MT, Eckner KL, Kozak S, Kabat D, Geib RW. Mutations in the env gene of friend spleen focus-forming virus overcome Fv-2r-mediated resistance to Friend virus-induced erythroleukemia. J Virol. 1992 Jun;66(6):3652–3660. [PMC free article] [PubMed]
  • Metcalf D. The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature. 1989 May 4;339(6219):27–30. [PubMed]
  • Miura O, D'Andrea A, Kabat D, Ihle JN. Induction of tyrosine phosphorylation by the erythropoietin receptor correlates with mitogenesis. Mol Cell Biol. 1991 Oct;11(10):4895–4902. [PMC free article] [PubMed]
  • Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 1992 Jun 26;69(7):1237–1245. [PubMed]
  • Moreau-Gachelin F, Ray D, Mattei MG, Tambourin P, Tavitian A. The putative oncogene Spi-1: murine chromosomal localization and transcriptional activation in murine acute erythroleukemias. Oncogene. 1989 Dec;4(12):1449–1456. [PubMed]
  • Moreau-Gachelin F, Tavitian A, Tambourin P. Spi-1 is a putative oncogene in virally induced murine erythroleukaemias. Nature. 1988 Jan 21;331(6153):277–280. [PubMed]
  • Mowat M, Cheng A, Kimura N, Bernstein A, Benchimol S. Rearrangements of the cellular p53 gene in erythroleukaemic cells transformed by Friend virus. Nature. 1985 Apr 18;314(6012):633–636. [PubMed]
  • Nishikawa S, Kusakabe M, Yoshinaga K, Ogawa M, Hayashi S, Kunisada T, Era T, Sakakura T, Nishikawa S. In utero manipulation of coat color formation by a monoclonal anti-c-kit antibody: two distinct waves of c-kit-dependency during melanocyte development. EMBO J. 1991 Aug;10(8):2111–2118. [PMC free article] [PubMed]
  • Nocka K, Majumder S, Chabot B, Ray P, Cervone M, Bernstein A, Besmer P. Expression of c-kit gene products in known cellular targets of W mutations in normal and W mutant mice--evidence for an impaired c-kit kinase in mutant mice. Genes Dev. 1989 Jun;3(6):816–826. [PubMed]
  • Nunn MF, Seeburg PH, Moscovici C, Duesberg PH. Tripartite structure of the avian erythroblastosis virus E26 transforming gene. Nature. 1983 Nov 24;306(5941):391–395. [PubMed]
  • Oettinger MA, Schatz DG, Gorka C, Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990 Jun 22;248(4962):1517–1523. [PubMed]
  • Orkin SH. Globin gene regulation and switching: circa 1990. Cell. 1990 Nov 16;63(4):665–672. [PubMed]
  • Paul R, Schuetze S, Kozak SL, Kabat D. A common site for immortalizing proviral integrations in Friend erythroleukemia: molecular cloning and characterization. J Virol. 1989 Nov;63(11):4958–4961. [PMC free article] [PubMed]
  • Paul R, Schuetze S, Kozak SL, Kozak CA, Kabat D. The Sfpi-1 proviral integration site of Friend erythroleukemia encodes the ets-related transcription factor Pu.1. J Virol. 1991 Jan;65(1):464–467. [PMC free article] [PubMed]
  • Pharr PN, Hankins D, Hofbauer A, Lodish HF, Longmore GD. Expression of a constitutively active erythropoietin receptor in primary hematopoietic progenitors abrogates erythropoietin dependence and enhances erythroid colony-forming unit, erythroid burst-forming unit, and granulocyte/macrophage progenitor growth. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):938–942. [PMC free article] [PubMed]
  • Ruscetti SK, Janesch NJ, Chakraborti A, Sawyer ST, Hankins WD. Friend spleen focus-forming virus induces factor independence in an erythropoietin-dependent erythroleukemia cell line. J Virol. 1990 Mar;64(3):1057–1062. [PMC free article] [PubMed]
  • Ruta M, Clarke S, Boswell B, Kabat D. Heterogeneous metabolism and subcellular localization of a potentially leukemogenic membrane glycoprotein encoded by Friend erythroleukemia virus. Isolation of viral and cellular processing mutants. J Biol Chem. 1982 Jan 10;257(1):126–134. [PubMed]
  • Sawada K, Krantz SB, Dai CH, Koury ST, Horn ST, Glick AD, Civin CI. Purification of human blood burst-forming units-erythroid and demonstration of the evolution of erythropoietin receptors. J Cell Physiol. 1990 Feb;142(2):219–230. [PubMed]
  • Schatz DG, Oettinger MA, Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell. 1989 Dec 22;59(6):1035–1048. [PubMed]
  • Semenza GL, Traystman MD, Gearhart JD, Antonarakis SE. Polycythemia in transgenic mice expressing the human erythropoietin gene. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2301–2305. [PMC free article] [PubMed]
  • Sherr CJ, Rettenmier CW, Sacca R, Roussel MF, Look AT, Stanley ER. The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1. Cell. 1985 Jul;41(3):665–676. [PubMed]
  • Troxler DH, Boyars JK, Parks WP, Scolnick EM. Friend strain of spleen focus-forming virus: a recombinant between mouse type C ecotropic viral sequences and sequences related to xenotropic virus. J Virol. 1977 May;22(2):361–372. [PMC free article] [PubMed]
  • van Lohuizen M, Berns A. Tumorigenesis by slow-transforming retroviruses--an update. Biochim Biophys Acta. 1990 Dec 11;1032(2-3):213–235. [PubMed]
  • van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H, Berns A. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell. 1991 May 31;65(5):737–752. [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]
  • Wolff L, Koller R, Ruscetti S. Monoclonal antibody to spleen focus-forming virus-encoded gp52 provides a probe for the amino-terminal region of retroviral envelope proteins that confers dual tropism and xenotropism. J Virol. 1982 Aug;43(2):472–481. [PMC free article] [PubMed]
  • Yoshimura A, D'Andrea AD, Lodish HF. Friend spleen focus-forming virus glycoprotein gp55 interacts with the erythropoietin receptor in the endoplasmic reticulum and affects receptor metabolism. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4139–4143. [PMC free article] [PubMed]
  • Youssoufian H, Longmore G, Neumann D, Yoshimura A, Lodish HF. Structure, function, and activation of the erythropoietin receptor. Blood. 1993 May 1;81(9):2223–2236. [PubMed]

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

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...