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Differential regulation of SOCS genes in normal and transformed erythroid cells

Oncogene volume 22, pages 3221–3230 (2003)Cite this article

Abstract

The SOCS family of genes are negative regulators of cytokine signalling with SOCS-1 displaying tumor suppressor activity. SOCS-1, CIS and SOCS-3 have been implicated in the regulation of red blood cell production. In this study, a detailed examination was conducted on the expression patterns of these three SOCS family members in normal erythroid progenitors and a panel of erythroleukemic cell lines. Unexpectedly, differences in SOCS gene expression were observed during maturation of normal red cell progenitors, viz changes to CIS were inversely related to the alterations of SOCS-1 and SOCS-3. Similarly, these SOCS genes were differentially expressed in transformed erythoid cells – erythroleukemic cells immortalized at an immature stage of differentiation expressed SOCS-1 and SOCS-3 mRNA constitutively, whereas in more mature cell lines SOCS-1 and CIS were induced only after exposure to erythropoietin (Epo). Significantly, when ectopic expression of the tyrosine kinase Lyn was used to promote differentiation of immature cell lines, constitutive expression of SOCS-1 and SOCS-3 was completely suppressed. Modulation of intracellular signalling via mutated Epo receptors in mature erythroleukemic lines also highlighted different responses by the three SOCS family members. Close scrutiny of SOCS-1 revealed that, despite large increases in mRNA levels, the activity of the promoter did not alter after erythropoietin stimulation; in addition, erythroid cells from SOCS-1−/− mice displayed increased sensitivity to Epo. These observations indicate complex, stage-specific regulation of SOCS genes during normal erythroid maturation and in erythroleukemic cells.

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Acknowledgements

We acknowledge the expert technical assistance from Shane Meakins, Research Centre, Royal Perth Hospital. Recombinant human Epo (Eprex) was a generous gift from Dr J Adams and Dr J Patava (Janssen-Cilag, Australia). This work was supported by grants from NHMRC (#99-0596 and the Block Grant to the Walter and Eliza Hall Institute), the Cancer Foundation of Western Australia, the Medical Research Foundation of Royal Perth Hospital, The Neurotrauma Research Program of Western Australia, the National Institutes of Health, Bethesda, Maryland (Grant CA-22556), National Cancer Institute and The National Institutes of Health, Bethesda, Maryland (Grant CA-77447). SJB is an NHMRC RD Wright Postdoctoral Fellow. RS was supported by a Postdoctoral Fellowship from the Australian Research Council.

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Authors and Affiliations

  1. Laboratory for Cancer Medicine, Western Australian Institute for Medical Research, Royal Perth Hospital and Centre for Medical Research, The University of Western Australia, Perth, Australia

    Mohinder K Sarna, Evan Ingley, Vanessa S Cull, Winald Lepere, David J McCarthy, Michael J Wright, Gene A Palmer, David Chappell, Melissa S Sayer, S Peter Klinken & Peta A Tilbrook

  2. Neurotrauma Laboratory, Western Australian Institute for Medical Research, Royal Perth Hospital, Australia

    Samantha J Busfield

  3. Walter and Eliza Hall Institute of Medical Research and The Cooperative Research Center for Cellular Growth Factors, PO Box Royal Melbourne Hospital, Melbourne, Australia

    Warren S Alexander, Douglas J Hilton & Robyn Starr

  4. Department of Immunology, MD Anderson Cancer Centre, Houston, TX, USA

    Stephanie S Watowich

  5. Institute of Medical Biochemistry, University of Rostock, Rostock, Germany

    Winald Lepere & Thomas Bittorf

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Correspondence to S Peter Klinken.

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Sarna, M., Ingley, E., Busfield, S. et al. Differential regulation of SOCS genes in normal and transformed erythroid cells. Oncogene 22, 3221–3230 (2003). https://doi.org/10.1038/sj.onc.1206381

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