title: Effects of parathyroid hormone-related protein and macrophage inflammatory protein-1α in Jurkat T-cells on tumor formation in vivo and expression of apoptosis regulatory genes in vitro.
abstract: Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) have been implicated in the pathogenesis of adult T-cell leukemia/lymphoma, but their effects on T-cells have not been well studied. Here we analyzed the functions of PTHrP and MIP-1α on T-cell growth and death both in vitro and in vivo by overexpressing either factor in human Jurkat T-cells. PTHrP or MIP-1α did not affect Jurkat cell growth in vitro, but PTHrP increased their sensitivity to apoptosis. Importantly, PTHrP and MIP-1α decreased both tumor incidence and growth in vivo. To investigate possible mechanisms, polymerase chain reaction (PCR) arrays and real-time reverse transcription (RT)-PCR assays were performed. Both PTHrP and MIP-1α increased the expression of several factors including signal transducer and activator of transcription 4, tumor necrosis factor α, receptor activator of nuclear factor κB ligand and death-associated protein kinase 1, and decreased the expression of inhibitor of DNA binding 1, interferon γ and CD40 ligand in Jurkat cells. In addition, MIP-1α also increased the expression of transcription factor AP-2α and PTHrP increased expression of the vitamin D3 receptor. These data demonstrate that PTHrP and MIP-1α exert a profound antitumor effect presumably by increasing the sensitivity to apoptotic signals through modulation of transcription and apoptosis factors in T-cells.
authors.affiliation: Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Sherry T
authors.initials: ST
authors.lastname: Shu
authors.forename: Wessel P
authors.initials: WP
authors.lastname: Dirksen
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Lanigan
authors.forename: Chelsea K
authors.initials: CK
authors.lastname: Martin
authors.forename: Nanda K
authors.initials: NK
authors.lastname: Thudi
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Werbeck
authors.forename: Soledad A
authors.initials: SA
authors.lastname: Fernandez
authors.forename: Blake E
authors.initials: BE
authors.lastname: Hildreth
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D023201:CD40 Ligand / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D045744:Cell Line, Tumor; D054405:Chemokine CCL3 / Q000235:genetics*; D064550:Death-Associated Protein Kinases; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D019169:Jurkat Cells; D007942:Leukemia, Experimental / Q000235:genetics* / Q000473:pathology; D015458:Leukemia, T-Cell / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics*; D053245:RANK Ligand / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050797:STAT4 Transcription Factor / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D054405:Chemokine CCL3; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; D050797:STAT4 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D007371:Interferon-gamma; C579096:DAPK1 protein, human; C579106:Dapk1 protein, mouse; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases