1. ¹Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA
2. ²Center for Retrovirus Research, The Ohio State University, Columbus, OH, USA
3. ³Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH, USA
4. ⁴State University of New York Upstate Medical University, Syracuse, NY, USA
5. ⁵Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA

Correspondence: Professor TJ Rosol, Department of Veterinary Biosciences, The Ohio State University, Goss Lab, 1925 Coffey road, Columbus, OH 43210, USA. Fax: +1 614 292 6473; E-mail: rosol.1@osu.edu

Received 20 January 2005; Accepted 1 April 2005; Published online 12 May 2005.

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.