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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ritchie, A. Articles by Broxmeyer, H. E. Search for Related Content PubMed PubMed Citation Articles by Ritchie, A. Articles by Broxmeyer, H. E. Related Collections Hematopoiesis and Stem Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Thrombopoietin Upregulates the Promoter Conformation of p53 in a Proliferation-Independent Manner Coincident With a Decreased Expression of Bax: Potential Mechanisms for Survival Enhancing Effects Alec Ritchie, Akihiko Gotoh, Jay Gaddy, Stephen E. Braun, and Hal E. Broxmeyer From the Departments of Microbiology/Immunology, Medicine (Hematology/Oncology), and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN. Thrombopoietin (Tpo) has proliferative and maturational effects on immature and more committed cells, respectively. We previously reported a role for Tpo as a survival factor in the factor-dependent human cell line M07e by demonstrating that Tpo suppresses apoptosis in the absence of induced proliferation. Wild-type p53 is a tumor suppressor gene that can play a vital role in mediating growth factor withdrawal-induced apoptosis in factor-dependent hematopoietic cells. Wild-type p53 can switch from a suppressor conformation, with an antiproliferative, pro-apoptotic phenotype, to a promoter conformation that has a diminished ability to mediate cell cycle arrest and apoptosis. In an effort to elucidate the mechanisms through which Tpo suppresses apoptosis, we investigated the effects of Tpo treatment on p53-mediated apoptosis in M07e cells. Tpo upregulated the expression of the promoter conformation of p53 in M07e cells coincident with a downregulation of Bax and Mdm2 protein levels. Protein levels of Bcl-2 and Bcl-xL did not significantly vary as a function of growth-factor stimulation. Conversely, the levels of suppressor conformation p53 were maximal when M07e was in a growth arrested state and decreased during factor stimulation. Furthermore, Tpo treatment induced an extranuclear buildup and greatly weakened the DNA binding capacity of p53. p53-specific antisense oligonucleotide treatment recapitulated the effects of Tpo treatment on the levels of Bax, Mdm-2, and Bcl-2. These results suggest that Tpo is suppressing growth factor withdrawal induced-apoptosis, at least in part, by downregulating the expression of pro-apoptotic Bax protein levels, through modulating the conformation of p53, which results in a functional inactivation of its pro-apoptotic abilities. Blood, Vol. 90 No. 11 (December 1), 1997: pp. 4394-4402 © 1997 by The American Society of Hematology. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Dainiak, J. K. Waselenko, J. O. Armitage, T. J. MacVittie, and A. M. Farese The Hematologist and Radiation Casualties Hematology, January 1, 2003; 2003(1): 473 - 496. [Abstract] [Full Text] [PDF] S M Aronica, A Dozier, P Fanti, and M Nazareth Altered bone marrow cell sensitivity in the lupus-prone NZB/W mouse: regulation of CFU-GM colony formation by estrogen, tamoxifen and thrombopoietin Lupus, May 1, 2000; 9(4): 271 - 277. [Abstract] [PDF] R. S. Schwartz Polycythemia Vera -- Chance, Death, and Mutability N. Engl. J. Med., February 26, 1998; 338(9): 613 - 615. [Full Text]

	Copyright © 1997 by American Society of Hematology         Online ISSN: 1528-0020