Transcriptional regulation of parathyroid hormone-related protein promoter P3 by ETS-1 in adult T-cell leukemia/lymphoma.
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.
Richard
V
V
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.
Nadella
M V P
MV
Green
P L
PL
Lairmore
M D
MD
Feuer
G
G
Foley
J G
JG
Rosol
T J
TJ
D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016370:Gene Products, rex / Q000235:genetics / Q000378:metabolism; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism; D015490:HTLV-I Infections / Q000378:metabolism / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D008297:Male; D051379:Mice; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
C494041:ETS1 protein, human; C494042:Ets1 protein, mouse; D016370:Gene Products, rex; D016356:Gene Products, tax; D044162:Parathyroid Hormone-Related Protein; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases