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

V. Richard, M. V P Nadella, P. L. Green, Michael Dale Lairmore, G. Feuer, J. G. Foley, T. J. Rosol

Research output: Contribution to journalArticle

16 Scopus citations

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 upregullated 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.

Original languageEnglish (US)
Pages (from-to)1175-1183
Number of pages9
JournalLeukemia
Volume19
Issue number7
DOIs
StatePublished - Jul 2005
Externally publishedYes

Keywords

  • Adult T-cell leukemia/lymphoma (ATLL)
  • ETS-1
  • HTLV-1
  • Humoral hypercalcemia of malignancy (HHM)
  • Parathyroid hormone-related protein (PTHrP)
  • Transcriptional regulation

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

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