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 language | English (US) |
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Pages (from-to) | 1752-1762 |
Number of pages | 11 |
Journal | Leukemia |
Volume | 21 |
Issue number | 8 |
DOIs | |
State | Published - Aug 2007 |
Externally published | Yes |
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research