title: Lineage-specific induction of B cell apoptosis and altered signal transduction by the phosphotyrosine phosphatase inhibitor bis(maltolato)oxovanadium(IV).
abstract: Protein tyrosine phosphorylation is known to play key roles in lymphocyte signal transduction, and phosphotyrosine phosphatases (PTP) can act as both positive and negative regulators of these lymphocyte signals. We sought to examine the role of PTP further in these processes by characterizing the effects of bis(maltolato)-oxovanadium(IV) (BMLOV), previously known to be a nontoxic insulin mimetic agent in vivo. BMLOV was found to be a potent phosphotyrosine phosphatase inhibitor. BMLOV induced cellular tyrosine phosphorylation in B cells in a pattern similar to that observed following antigen receptor stimulation, whereas little tyrosine phosphorylation was induced in T cells. In B cells, BMLOV treatment resulted in tyrosine phosphorylation of Syk and phospholipase C gamma 2, while sIgM-induced signals were inhibited. By contrast, T cell receptor signals were moderately increased by BMLOV, and the cells displayed greater induction of IL-2 receptor without toxicity. The compound selectively induced apoptosis in B cell lymphoma and myeloid leukemia cell lines, but not in T cell leukemia or colon carcinoma cells. Interleukin-4 plus anti-CD40 antibody treatment of normal human peripheral B cells rescued the cells from BMLOV-induced death. These results suggest that phosphotyrosine phosphatase inhibitors can activate B cell signal pathways in a lineage-specific manner, resulting in desensitization of receptor-mediated signaling and induction of apoptosis.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Schieven
authors.forename: A F
authors.initials: AF
authors.lastname: Wahl
authors.forename: S
authors.initials: S
authors.lastname: Myrdal
authors.forename: L
authors.initials: L
authors.lastname: Grosmaire
authors.forename: J A
authors.initials: JA
authors.lastname: Ledbetter
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007075:Immunoglobulin M / Q000502:physiology; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute; D015458:Leukemia, T-Cell; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell; D051379:Mice; D010740:Phospholipases / Q000378:metabolism; D010835:Phytohemagglutinins; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology*; D011947:Receptors, Antigen, B-Cell / Q000187:drug effects / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*; D053634:TYK2 Kinase; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D007075:Immunoglobulin M; D010835:Phytohemagglutinins; D011506:Proteins; D011753:Pyrones; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; C033027:secretory IgM; C074212:bis(maltolato)oxovanadium(IV); D014638:Vanadates; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse; D010740:Phospholipases; D017027:Protein Tyrosine Phosphatases; D002118:Calcium