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Granulocyte colony-stimulating factor-induced upregulation of Jak3 transcription during granulocytic differentiation is mediated by the cooperative action of Sp1 and Stat3

Oncogene volume 25, pages 2489–2499 (2006)Cite this article

Abstract

We previously demonstrated that Jak3 is a primary response gene for G-CSF and ectopic overexpression of Jak3 can accelerate granulocytic differentiation of normal mouse bone marrow cells induced by G-CSF and GM-CSF. To gain insight into the regulation of G-CSF-induced transcription of Jak3, we constructed deletion and linker scanning mutants of the Jak3 promoter sequences and performed luciferase reporter assays in the murine myeloid cell line 32Dcl3, with and without G-CSF stimulation. These experiments showed that mutation of a −67 to −85 element, which contained a putative Sp1 binding site, or mutation of a −44 to −53 GAS element resulted in a marked reduction of Jak3 promoter activity. Electrophoretic mobility shift assays revealed that Sp1 and Stat3 present in nuclear lysates of 32Dcl3 cells stimulated with G-CSF can bind to the −67 to −85 element and −44 to −53 GAS element, respectively. In addition, cotransfection of a constitutively active mutant of Stat3 along with a Jak3 promoter/luciferase reporter resulted in enhanced Jak3 promoter activity. Together, these results demonstrate that activation of Jak3 transcription during G-CSF- induced granulocytic differentiation is mediated by the combined action of Sp1 and Stat3, a mechanism also shown to be important in IL-6-induced monocytic differentiation.

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Acknowledgements

We thank Dr Atul Kumar for obtaining the genomic clone of the Jak3 promoter. We thank Dr Anita L Korapati for construction of the Stat3-C mutant and establishment of the 32Dcl3/Stat3-C cell line. This research was supported by grants CA68239, CA79086, ES09225, and R24 CA88261 from the National Institutes of Health to EPR.

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Author notes

  1. J K Mangan

    Present address: Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, 48109, USA

  2. S G Rane

    Present address: Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute/National Institutes of Health, Bethesda, MD, 20892, USA

Authors and Affiliations

  1. Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA

    J K Mangan, R V Tantravahi, S G Rane & E P Reddy

  2. Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA

    S G Rane & E P Reddy

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Correspondence to E P Reddy.

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Mangan, J., Tantravahi, R., Rane, S. et al. Granulocyte colony-stimulating factor-induced upregulation of Jak3 transcription during granulocytic differentiation is mediated by the cooperative action of Sp1 and Stat3. Oncogene 25, 2489–2499 (2006). https://doi.org/10.1038/sj.onc.1209280

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