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Adult T Cell Leukemia

Transcriptional regulation of parathyroid hormone-related protein promoter P3 by ETS-1 in adult T-cell leukemia/lymphoma

Leukemia volume 19, pages 1175–1183 (2005)Cite this article

Abstract

Parathyroid hormone-related protein (PTHrP) plays a primary role in the development of humoral hypercalcemia of malignancy seen in the majority of adult T-cell leukemia/lymphoma (ATLL) patients with human T-cell lymphotropic virus type-1 (HTLV-1) infection. HTLV-1 Tax has been shown to complex with ETS-1 and SP1 to transactivate the PTHrP P3 promoter. Previously, we established a SCID/bg mouse model of human ATL with RV-ATL cells and showed that PTHrP expression was independent of Tax. In this study, we report an inverse correlation of PTHrP with tax/rex mRNA in multiple HTLV-1-positive cell lines and RV-ATL cells. Stimulation of Jurkat T cells with PMA/ionomycin upregulated the PTHrP P3 promoter by a previously characterized Ets binding site and also induced protein/DNA complex formation identical to that observed in RV-ATL cells. Further, we provide evidence that cotransfection with Ets-1 and constitutively active Mek-1 in HTLV-1-negative transformed T cells with stimulation by PMA/ionomycin not only resulted in a robust induction of PTHrP P3 but also formed a complex with ETS-1/P3 EBS similar to that in ATLL cells. Our data demonstrate that transcriptional regulation of PTHrP in ATLL cells can be controlled by T-cell receptor signaling and the ETS and MAPK ERK pathway in a Tax-independent manner.

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Authors and Affiliations

  1. Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA

    V Richard, M V P Nadella, P L Green, M D Lairmore & T J Rosol

  2. Center for Retrovirus Research, The Ohio State University, Columbus, OH, USA

    P L Green, M D Lairmore & T J Rosol

  3. Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH, USA

    P L Green, M D Lairmore & T J Rosol

  4. State University of New York Upstate Medical University, Syracuse, NY, USA

    G Feuer

  5. Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA

    J G Foley

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Correspondence to T J Rosol.

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This work was supported by the National Cancer Institute (CA100730 and CA77911) and the National Center for Research Resources (RR00168). VR and MVPN were supported by the Barber Trust Fund from the College of Veterinary Medicine, The Ohio State University.

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Richard, V., Nadella, M., Green, P. et al. Transcriptional regulation of parathyroid hormone-related protein promoter P3 by ETS-1 in adult T-cell leukemia/lymphoma. Leukemia 19, 1175–1183 (2005). https://doi.org/10.1038/sj.leu.2403787

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