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Thrombopoietin-induced conformational change in p53 lies downstream of the p44/p42 mitogen activated protein kinase cascade in the human growth factor-dependent cell line M07e

Oncogene volume 18, pages 1465–1477 (1999)Cite this article

Abstract

Thrombopoietin is a cytokine with potent megakaryocytopoietic and thrombopoietic activities in vivo. Wild-type p53 is a conformationally flexible, anti-oncogenic transcription factor that plays a principal role in mediating growth factor withdrawal-induced apoptosis in factor-dependent hematopoietic cells. We recently reported that Tpo induces a conformational change in and functional inactivation of p53, coincident with its anti-apoptotic effects, in the human factor-dependent cell line M07e. In an effort to identify potential signaling cascades through which Tpo illicits these effects on p53, we report here that treating M07e cells with MAPK kinase inhibitor PD98059 dramatically suppressed Tpo-induced conformational change in p53 as well as Tpo-enhanced viability in M07e cells in a p53-dependent manner. Furthermore, the expression of constitutively active Raf1 in M07e cells induced conformational change in p53 independent of Tpo stimulation. Inhibition of the JAK/STAT pathway revealed that JAK/STAT signaling plays an insignificant role in conformational modulation of p53 and apoptosis suppression. Inhibition of phosphatidylinositol-3 kinase did not have a significant effect on p53 conformation but did have a weak but significant effect on Tpo-enhanced viability. Cytokine-induced activation of the MAPK pathway and the subsequent functional neutralization of p53, may be an event by which apoptosis is commonly suppressed in hematopoiesis.

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Acknowledgements

These studies were supported by Public Health Service grants RO1 HL 56416, RO1 HL 54037, RO1 DK 53674 and by a project in PO1 HL 53586 from the National Institutes of Health to HEB. AR is supported by NIH training program T32 DK 07519 to HEB. The authors wish to thank Rebecca Miller, Linda Chung, and Cynthia Booth for their excellent secretarial and administrative support.

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  1. Alec Ritchie

    Present address: Department of Vascular Biology, The Scripps Research Institute, 10666 N. Torrey Pines Rd, La Jolla, CA, 92037, USA

Authors and Affiliations

  1. Department of Microbiology/Immunology, Indiana University School of Medicine, 46202, Indianapolis, USA

    Alec Ritchie, Stephen E Braun, Johnny He & Hal E Broxmeyer

  2. Department of Medicine (Hematology/Oncology), Indiana University School of Medicine, 46202, Indianapolis, USA

    Alec Ritchie & Hal E Broxmeyer

  3. Walther Oncology Center, Indiana University School of Medicine, 46202, Indianapolis, USA

    Alec Ritchie, Stephen E Braun, Johnny He & Hal E Broxmeyer

  4. Walther Cancer Institute, Indianapolis, 42208, Indiana, USA

    Alec Ritchie, Stephen E Braun, Johnny He & Hal E Broxmeyer

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Ritchie, A., Braun, S., He, J. et al. Thrombopoietin-induced conformational change in p53 lies downstream of the p44/p42 mitogen activated protein kinase cascade in the human growth factor-dependent cell line M07e. Oncogene 18, 1465–1477 (1999). https://doi.org/10.1038/sj.onc.1202439

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