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

Leukemia. 2007 Aug;21(8):1752-62. doi: 10.1038/sj.leu.2404798. Epub 2007 Jun 7.


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-kappaB (NF-kappaB) 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-kappaB expression plasmids and PTHrP P2 luciferase reporter-plasmid, we showed that NF-kappaB p50/p50 alone and p50/c-Rel or p50/Bcl-3 cooperatively upregulated the PTHrP P2 promoter. Furthermore, inhibition of NF-kappaB 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-kappaB activation and also suggest a Tax-independent mechanism of activation of PTHrP in ATLL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Chloramphenicol O-Acetyltransferase
  • Chromatin Immunoprecipitation
  • Electrophoretic Mobility Shift Assay
  • Gene Expression Regulation, Neoplastic*
  • HTLV-I Infections / metabolism
  • HTLV-I Infections / virology
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell / genetics*
  • Leukemia-Lymphoma, Adult T-Cell / metabolism
  • Leukemia-Lymphoma, Adult T-Cell / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutagenesis, Site-Directed
  • NF-kappa B / physiology*
  • Parathyroid Hormone-Related Protein / genetics*
  • Parathyroid Hormone-Related Protein / metabolism
  • Plasmids
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcriptional Activation
  • Transfection


  • NF-kappa B
  • Parathyroid Hormone-Related Protein
  • RNA, Messenger
  • Chloramphenicol O-Acetyltransferase