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 upregulated 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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Animals
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Cell Line, Tumor
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Products, rex / genetics
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Gene Products, rex / metabolism
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Gene Products, tax / genetics
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Gene Products, tax / metabolism
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HTLV-I Infections / metabolism
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HTLV-I Infections / virology
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Human T-lymphotropic virus 1 / genetics
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Human T-lymphotropic virus 1 / metabolism
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Humans
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Leukemia-Lymphoma, Adult T-Cell / genetics
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Leukemia-Lymphoma, Adult T-Cell / metabolism*
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Leukemia-Lymphoma, Adult T-Cell / virology
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Male
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Mice
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Parathyroid Hormone-Related Protein / genetics
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Parathyroid Hormone-Related Protein / metabolism*
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Promoter Regions, Genetic*
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-ets
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Antigen, T-Cell / metabolism
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Signal Transduction / physiology
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic*
Substances
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ETS1 protein, human
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Ets1 protein, mouse
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Gene Products, rex
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Gene Products, tax
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Parathyroid Hormone-Related Protein
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-ets
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RNA, Messenger
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Receptors, Antigen, T-Cell
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Transcription Factors
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Extracellular Signal-Regulated MAP Kinases