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  • Original Paper
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STAT3-mediated differentiation and survival of myeloid cells in response to granulocyte colony-stimulating factor: role for the cyclin-dependent kinase inhibitor p27Kip1

Oncogene volume 19, pages 3290–3298 (2000)Cite this article

Abstract

The signal transducer and activator of transcription (STAT) proteins have been implicated in cytokine-regulated proliferation, differentiation and cell survival. Granulocyte colony-stimulating factor (G-CSF), a regulator of granulocytic differentiation, induces a robust and sustained activation of STAT3. Here, we show that introduction of dominant negative (DN) forms of STAT3 interferes with G-CSF-induced differentiation and survival in murine 32D cells. G-CSF induces expression of the cyclin-dependent kinase (cdk) inhibitor p27Kip1 (but not p21Cip1), which is completely blocked by DN-STAT3. The ability of tyrosine-to-phenylalanine substitution mutants of the G-CSF receptor to activate STAT3 strongly correlated with their capacity to induce p27 expression and their ability to mediate differentiation and survival, suggesting a causal relationship between STAT3 activation, p27 expression and the observed cellular responses. We identified a putative STAT binding site in the promoter region of p27 that showed both STAT3 binding in electrophoretic mobility shift assays and functional activity in luciferase reporter assays. Finally, we studied G-CSF-induced responses in primary bone marrow and spleen cells of p27-deficient mice. Compared with wild-type, myeloid progenitors from p27-deficient mice showed significantly increased proliferation and reduced differentiation in response to G-CSF. These findings indicate that STAT3 controls myeloid differentiation, at least partly, via upregulation of p27Kip1.

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Acknowledgements

We thank L Smith, J Gits, C Erpelinck, S Oomen and M Hermans for excellent technical advice and assistance, M von Lindern for critical reading of the manuscript, K Nakajima and T Hirano for STAT3 plasmids, A Nordin for the p27Kip1-pGL-2 construct, T Hunter for murine p27Kip1 cDNA, G Gil Gomez and J Roberts for p27-deficient mice, R Bernards for anti-p27Kip1 antibodies, and K van Rooyen for exquisite graphical work. This work was supported by grants from the Dutch Cancer Society ‘Koningin Wilhelmina Fonds’, the Netherlands Organization for Scientific Research (NWO) and an EMBO Long Term Fellowship.

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Authors and Affiliations

  1. Institute of Hematology, Erasmus University, P.O. Box 1738, Rotterdam, 3000, DR, The Netherlands

    John P de Koning, Amrita A Soede-Bobok, Alister C Ward, Claudia Antonissen, Bob Löwenberg & Ivo P Touw

  2. Department of Hematology, Dr Daniel den Hoed Cancer Center, P.O. Box 5201, Rotterdam, 3008, AE, The Netherlands

    Anita M Schelen, Daphne van Leeuwen, Bob Löwenberg & Ivo P Touw

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  1. John P de Koning
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de Koning, J., Soede-Bobok, A., Ward, A. et al. STAT3-mediated differentiation and survival of myeloid cells in response to granulocyte colony-stimulating factor: role for the cyclin-dependent kinase inhibitor p27Kip1. Oncogene 19, 3290–3298 (2000). https://doi.org/10.1038/sj.onc.1203627

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