Transcriptional regulation of parathyroid hormone-related protein promoter P2 by NF-κB in adult T-cell leukemia/lymphoma

M. V.P. Nadella, W. P. Dirksen, K. S. Nadella, S. Shu, A. S. Cheng, J. A. Morgenstern, V. Richard, S. A. Fernandez, T. H. Huang, D. Guttridge, T. J. Rosol

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Parathyroid hormone-related protein (PTHrP) plays a primary role in the development of humoral hypercalcemia of malignancy (HHM) that occurs in the majority of patients with adult T-cell leukemia/lymphoma (ATLL) due to human T-cell lymphotropic virus type-1 (HTLV-1) infection. We previously showed that ATLL cells constitutively express high levels of PTHrP via activation of promoters P2 and P3, resulting in HHM. In this study, we characterized a nuclear factor-κB (NF-κB) binding site in the P2 promoter of human PTHrP. Using electrophoretic mobility shift assays, we detected a specific complex in Tax-expressing human T cells composed of p50/c-Rel, and two distinct complexes in ATLL cells consisting of p50/p50 homodimers and a second unidentified protein(s). Chromatin immunoprecipitation assays confirmed in vivo binding of p50 and c-Rel on the PTHrP P2 promoter. Using transient co-transfection with NF-κB expression plasmids and PTHrP P2 luciferase reporter-plasmid, we showed that NF-κB p50/p50 alone and p50/c-Rel or p50/Bcl-3 cooperatively upregulated the PTHrP P2 promoter. Furthermore, inhibition of NF-κB activity by Bay 11-7082 reduced PTHrP P2 promoter-initiated transcripts in HTLV-1-infected T cells. In summary, the data demonstrated that transcriptional regulation of PTHrP in ATLL cells can be controlled by NF-κB activation and also suggest a Tax-independent mechanism of activation of PTHrP in ATLL.

Original languageEnglish (US)
Pages (from-to)1752-1762
Number of pages11
JournalLeukemia
Volume21
Issue number8
DOIs
StatePublished - Aug 2007

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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