Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Aug 15;90(16):7864–7868. doi: 10.1073/pnas.90.16.7864

The SCL gene product is regulated by and differentially regulates cytokine responses during myeloid leukemic cell differentiation.

T Tanigawa 1, N Elwood 1, D Metcalf 1, D Cary 1, E DeLuca 1, N A Nicola 1, C G Begley 1
PMCID: PMC47243  PMID: 8356096

Abstract

Differentiation induction in murine M1 leukemia cells by interleukin 6 (IL-6), leukemia inhibitory factor (LIF), and oncostatin M (OSM) is postulated to occur via a common receptor chain, gp130. In this study, growth factor-induced differentiation of M1 cells was accompanied by a late and persistent decrease in levels of mRNA and protein for a helix-loop-helix transcription factor, the SCL gene product. To evaluate whether reduced SCL expression was instrumental in monocyte differentiation, an SCL cDNA expression vector was introduced into M1 cells to obtain cell lines in which overexpression of SCL mRNA and protein was enforced. This resulted in a reduction in cells differentiating in response to LIF and OSM but not in response to IL-6. Scatchard analysis indicated that both parental and SCL-transfected cell lines exhibited similar receptor numbers and receptor affinities for LIF, OSM, and IL-6, suggesting that the differential responsiveness was not due to selective receptor down-modulation. Thus, these data implicate SCL in monocytic differentiation and provide evidence for differential receptor signaling pathways despite utilization of a common gp130 subunit by all three receptors.

Full text

PDF
7864

Images in this article

7865Fig. 1
on p.7865
7865Fig. 2
on p.7865
7866Fig. 3
on p.7866

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aplan P. D., Nakahara K., Orkin S. H., Kirsch I. R. The SCL gene product: a positive regulator of erythroid differentiation. EMBO J. 1992 Nov;11(11):4073–4081. doi: 10.1002/j.1460-2075.1992.tb05500.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Begley C. G., Aplan P. D., Denning S. M., Haynes B. F., Waldmann T. A., Kirsch I. R. The gene SCL is expressed during early hematopoiesis and encodes a differentiation-related DNA-binding motif. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10128–10132. doi: 10.1073/pnas.86.24.10128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Begley C. G., Visvader J., Green A. R., Aplan P. D., Metcalf D., Kirsch I. R., Gough N. M. Molecular cloning and chromosomal localization of the murine homolog of the human helix-loop-helix gene SCL. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):869–873. doi: 10.1073/pnas.88.3.869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bernard O., Lecointe N., Jonveaux P., Souyri M., Mauchauffé M., Berger R., Larsen C. J., Mathieu-Mahul D. Two site-specific deletions and t(1;14) translocation restricted to human T-cell acute leukemias disrupt the 5' part of the tal-1 gene. Oncogene. 1991 Aug;6(8):1477–1488. [PubMed] [Google Scholar]
  5. Bruce A. G., Hoggatt I. H., Rose T. M. Oncostatin M is a differentiation factor for myeloid leukemia cells. J Immunol. 1992 Aug 15;149(4):1271–1275. [PubMed] [Google Scholar]
  6. Chen Q., Cheng J. T., Tasi L. H., Schneider N., Buchanan G., Carroll A., Crist W., Ozanne B., Siciliano M. J., Baer R. The tal gene undergoes chromosome translocation in T cell leukemia and potentially encodes a helix-loop-helix protein. EMBO J. 1990 Feb;9(2):415–424. doi: 10.1002/j.1460-2075.1990.tb08126.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cheng J. T., Cobb M. H., Baer R. Phosphorylation of the TAL1 oncoprotein by the extracellular-signal-regulated protein kinase ERK1. Mol Cell Biol. 1993 Feb;13(2):801–808. doi: 10.1128/mcb.13.2.801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cross M., Mangelsdorf I., Wedel A., Renkawitz R. Mouse lysozyme M gene: isolation, characterization, and expression studies. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6232–6236. doi: 10.1073/pnas.85.17.6232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gearing D. P., Bruce A. G. Oncostatin M binds the high-affinity leukemia inhibitory factor receptor. New Biol. 1992 Jan;4(1):61–65. [PubMed] [Google Scholar]
  10. Gearing D. P., Comeau M. R., Friend D. J., Gimpel S. D., Thut C. J., McGourty J., Brasher K. K., King J. A., Gillis S., Mosley B. The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Science. 1992 Mar 13;255(5050):1434–1437. doi: 10.1126/science.1542794. [DOI] [PubMed] [Google Scholar]
  11. Gearing D. P., Thut C. J., VandeBos T., Gimpel S. D., Delaney P. B., King J., Price V., Cosman D., Beckmann M. P. Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gp130. EMBO J. 1991 Oct;10(10):2839–2848. doi: 10.1002/j.1460-2075.1991.tb07833.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gonda T. J., Sheiness D. K., Bishop J. M. Transcripts from the cellular homologs of retroviral oncogenes: distribution among chicken tissues. Mol Cell Biol. 1982 Jun;2(6):617–624. doi: 10.1128/mcb.2.6.617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Green A. R., DeLuca E., Begley C. G. Antisense SCL suppresses self-renewal and enhances spontaneous erythroid differentiation of the human leukaemic cell line K562. EMBO J. 1991 Dec;10(13):4153–4158. doi: 10.1002/j.1460-2075.1991.tb04993.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Green A. R., Lints T., Visvader J., Harvey R., Begley C. G. SCL is coexpressed with GATA-1 in hemopoietic cells but is also expressed in developing brain. Oncogene. 1992 Apr;7(4):653–660. [PubMed] [Google Scholar]
  15. Green A. R., Rockman S., DeLuca E., Begley C. G. Induced myeloid differentiation of K562 cells with downregulation of erythroid and megakaryocytic transcription factors: a novel experimental model for hemopoietic lineage restriction. Exp Hematol. 1993 Apr;21(4):525–531. [PubMed] [Google Scholar]
  16. Green A. R., Salvaris E., Begley C. G. Erythroid expression of the 'helix-loop-helix' gene, SCL. Oncogene. 1991 Mar;6(3):475–479. [PubMed] [Google Scholar]
  17. Hariharan I. K., Adams J. M., Cory S. bcr-abl oncogene renders myeloid cell line factor independent: potential autocrine mechanism in chronic myeloid leukemia. Oncogene Res. 1988;3(4):387–399. [PubMed] [Google Scholar]
  18. Hibi M., Murakami M., Saito M., Hirano T., Taga T., Kishimoto T. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell. 1990 Dec 21;63(6):1149–1157. doi: 10.1016/0092-8674(90)90411-7. [DOI] [PubMed] [Google Scholar]
  19. Hilton D. J., Nicola N. A., Gough N. M., Metcalf D. Resolution and purification of three distinct factors produced by Krebs ascites cells which have differentiation-inducing activity on murine myeloid leukemic cell lines. J Biol Chem. 1988 Jul 5;263(19):9238–9243. [PubMed] [Google Scholar]
  20. Hilton D. J., Nicola N. A., Metcalf D. Specific binding of murine leukemia inhibitory factor to normal and leukemic monocytic cells. Proc Natl Acad Sci U S A. 1988 Aug;85(16):5971–5975. doi: 10.1073/pnas.85.16.5971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hoffman-Liebermann B., Liebermann D. A. Interleukin-6- and leukemia inhibitory factor-induced terminal differentiation of myeloid leukemia cells is blocked at an intermediate stage by constitutive c-myc. Mol Cell Biol. 1991 May;11(5):2375–2381. doi: 10.1128/mcb.11.5.2375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ichikawa Y. Differentiation of a cell line of myeloid leukemia. J Cell Physiol. 1969 Dec;74(3):223–234. doi: 10.1002/jcp.1040740303. [DOI] [PubMed] [Google Scholar]
  23. Ip N. Y., Nye S. H., Boulton T. G., Davis S., Taga T., Li Y., Birren S. J., Yasukawa K., Kishimoto T., Anderson D. J. CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor component gp130. Cell. 1992 Jun 26;69(7):1121–1132. doi: 10.1016/0092-8674(92)90634-o. [DOI] [PubMed] [Google Scholar]
  24. Kishimoto T., Akira S., Taga T. Interleukin-6 and its receptor: a paradigm for cytokines. Science. 1992 Oct 23;258(5082):593–597. doi: 10.1126/science.1411569. [DOI] [PubMed] [Google Scholar]
  25. Kouzarides T., Packham G., Cook A., Farrell P. J. The BZLF1 protein of EBV has a coiled coil dimerisation domain without a heptad leucine repeat but with homology to the C/EBP leucine zipper. Oncogene. 1991 Feb;6(2):195–204. [PubMed] [Google Scholar]
  26. Lord K. A., Abdollahi A., Thomas S. M., DeMarco M., Brugge J. S., Hoffman-Liebermann B., Liebermann D. A. Leukemia inhibitory factor and interleukin-6 trigger the same immediate early response, including tyrosine phosphorylation, upon induction of myeloid leukemia differentiation. Mol Cell Biol. 1991 Sep;11(9):4371–4379. doi: 10.1128/mcb.11.9.4371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Markowitz D., Goff S., Bank A. A safe packaging line for gene transfer: separating viral genes on two different plasmids. J Virol. 1988 Apr;62(4):1120–1124. doi: 10.1128/jvi.62.4.1120-1124.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Metcalf D. Actions and interactions of G-CSF, LIF, and IL-6 on normal and leukemic murine cells. Leukemia. 1989 May;3(5):349–355. [PubMed] [Google Scholar]
  29. Miyajima A., Hara T., Kitamura T. Common subunits of cytokine receptors and the functional redundancy of cytokines. Trends Biochem Sci. 1992 Oct;17(10):378–382. doi: 10.1016/0968-0004(92)90004-s. [DOI] [PubMed] [Google Scholar]
  30. Mouthon M. A., Bernard O., Mitjavila M. T., Romeo P. H., Vainchenker W., Mathieu-Mahul D. Expression of tal-1 and GATA-binding proteins during human hematopoiesis. Blood. 1993 Feb 1;81(3):647–655. [PubMed] [Google Scholar]
  31. Murre C., McCaw P. S., Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell. 1989 Mar 10;56(5):777–783. doi: 10.1016/0092-8674(89)90682-x. [DOI] [PubMed] [Google Scholar]
  32. Murre C., McCaw P. S., Vaessin H., Caudy M., Jan L. Y., Jan Y. N., Cabrera C. V., Buskin J. N., Hauschka S. D., Lassar A. B. Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell. 1989 Aug 11;58(3):537–544. doi: 10.1016/0092-8674(89)90434-0. [DOI] [PubMed] [Google Scholar]
  33. Nicola N. A., Cary D. Affinity conversion of receptors for colony stimulating factors: properties of solubilized receptors. Growth Factors. 1992;6(2):119–129. doi: 10.3109/08977199209011015. [DOI] [PubMed] [Google Scholar]
  34. Nicola N. A., Metcalf D. Binding, internalization, and degradation of 125I-multipotential colony-stimulating factor (interleukin-3) by FDCP-1 cells. Growth Factors. 1988;1(1):29–39. doi: 10.3109/08977198809000244. [DOI] [PubMed] [Google Scholar]
  35. Rose T. M., Bruce A. G. Oncostatin M is a member of a cytokine family that includes leukemia-inhibitory factor, granulocyte colony-stimulating factor, and interleukin 6. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8641–8645. doi: 10.1073/pnas.88.19.8641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Selvakumaran M., Liebermann D. A., Hoffman-Liebermann B. Deregulated c-myb disrupts interleukin-6- or leukemia inhibitory factor-induced myeloid differentiation prior to c-myc: role in leukemogenesis. Mol Cell Biol. 1992 Jun;12(6):2493–2500. doi: 10.1128/mcb.12.6.2493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Shabo Y., Lotem J., Rubinstein M., Revel M., Clark S. C., Wolf S. F., Kamen R., Sachs L. The myeloid blood cell differentiation-inducing protein MGI-2A is interleukin-6. Blood. 1988 Dec;72(6):2070–2073. [PubMed] [Google Scholar]
  38. Taga T., Hibi M., Hirata Y., Yamasaki K., Yasukawa K., Matsuda T., Hirano T., Kishimoto T. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989 Aug 11;58(3):573–581. doi: 10.1016/0092-8674(89)90438-8. [DOI] [PubMed] [Google Scholar]
  39. Thisse B., Stoetzel C., Gorostiza-Thisse C., Perrin-Schmitt F. Sequence of the twist gene and nuclear localization of its protein in endomesodermal cells of early Drosophila embryos. EMBO J. 1988 Jul;7(7):2175–2183. doi: 10.1002/j.1460-2075.1988.tb03056.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Tso J. Y., Sun X. H., Kao T. H., Reece K. S., Wu R. Isolation and characterization of rat and human glyceraldehyde-3-phosphate dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene. Nucleic Acids Res. 1985 Apr 11;13(7):2485–2502. doi: 10.1093/nar/13.7.2485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Visvader J., Begley C. G. Helix-loop-helix genes translocated in lymphoid leukemia. Trends Biochem Sci. 1991 Sep;16(9):330–333. doi: 10.1016/0968-0004(91)90137-k. [DOI] [PubMed] [Google Scholar]
  42. Yamaguchi M., Michishita M., Hirayoshi K., Yasukawa K., Okuma M., Nagata K. Down-regulation of interleukin 6 receptors of mouse myelomonocytic leukemic cells by leukemia inhibitory factor. J Biol Chem. 1992 Nov 5;267(31):22035–22042. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES