Expression and regulation of parathyroid hormone-related protein during lymphocyte transformation and development of humoral hypercalcemia of malignancy in lymphoma

 
 
 
 

Expression and regulation of parathyroid hormone-related protein during lymphocyte transformation and development of humoral hypercalcemia of malignancy in lymphoma

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Title: Expression and regulation of parathyroid hormone-related protein during lymphocyte transformation and development of humoral hypercalcemia of malignancy in lymphoma
Author: Nadella, Murali Vara Prasad
Description: Although adult T-cell leukemia/lymphoma (ATLL) is caused due to infection with human T-lymphotropic virus type-1 (HTLV-1), cellular events besides HTLV-1 infection are required for transformation of T-cells. HTLV-1 Tax plays an important role in the transformation of lymphocytes; however, the exact mechanisms remain unclear. Parathyroid hormone-related protein plays an important role in the pathogenesis of humoral hypercalcemia of malignancy observed in the majority of ATLL patients. PTHrP is also up-regulated in HTLV-1-carriers and normocalcemic ATLL patients. Using long-term co-culture assays, herein we reported that PTHrP and its receptor (PTH1R) were highly expressed during HTLV-1-mediated immortalization of lymphocytes. Co-transfection assays with HTLV-1 and PTHrP reporter plasmids showed that HTLV-1 mildly up-regulated PTHrP expression indicating that other cellular factors or events are required for increased expression of PTHrP in ATLL cells. The PTHrP gene is regulated by three promoter regions (P1, P2, and P3). We characterized an NF-êB binding site in the P2 promoter of human PTHrP and 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). Furthermore, we showed inhibition of NF-êB activity with Bay 11-7082 decreased PTHrP P2 promoter-initiated transcripts. Finally we developed a comparative xenograft model of canine T-cell lymphoma with hypercalcemia. Quantitative RT-PCR of T-cell lymphoma samples from hypercalcemic canine patients showed that PTHrP likely plays a central role in the pathogenesis of HHM and that hypercalcemia is the result of a combinatorial effect of different hypercalcemic factors. We monitored in vivo tumor progression and metastases in the mouse model by transducing the lymphoma cells with a lentiviral vector that encodes a luciferase-yellow fluorescent protein reporter and showed that in vivo trafficking patterns in this model were similar to that seen in dogs. These data demonstrated that 1) PTHrP and its receptor were markedly up-regulated during HTLV-1-mediated immortalization of lymphocytes 2) The PTHrP P2 promoter was regulated by NF-êB pathway in HTLV-1-infected and ATLL cells 3) Hypercalcemia in canine T-cell lymphoma patients was multifactorial and PTHrP plays an important role in the pathogenesis of HHM
Permanent Link: http://rave.ohiolink.edu/etdc/view?acc_num=osu1190131395
http://hdl.handle.net/2374.OX/8198
Date: 2007

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