Báo cáo y học: Inhibition of constitutively active Jak-Stat pathway suppresses cell growth of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells

Tuyển tập các báo cáo nghiên cứu về y học được đăng trên tạp chí y học quốc tế cung cấp cho các bạn kiến thức về ngành y đề tài: Inhibition of constitutively active Jak-Stat pathway suppresses cell growth of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells
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Báo cáo y học: " Inhibition of constitutively active Jak-Stat pathway suppresses cell growth of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells"Retrovirology BioMed Central Open AccessResearchInhibition of constitutively active Jak-Stat pathway suppresses cellgrowth of human T-cell leukemia virus type 1-infected T-cell linesand primary adult T-cell leukemia cellsMariko Tomita1, Hirochika Kawakami1, Jun-nosuke Uchihara1,2,Taeko Okudaira1,2, Masato Masuda2, Takehiro Matsuda1,3, Yuetsu Tanaka4,Kazuiku Ohshiro5 and Naoki Mori*1Address: 1Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara,Okinawa 903-0215, Japan, 2Division of Endocrinology and Metabolism, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara,Okinawa 903-0215, Japan, 3Division of Child Health and Welfare, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara,Okinawa 903-0215, Japan, 4Division of Immunology, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215,Japan and 5Department of Internal Medicine, Naha Prefectural Hospital, 1-3-1 Yogi, Naha, Okinawa 902-8531, JapanEmail: Mariko Tomita - mtomita@med.u-ryukyu.ac.jp; Hirochika Kawakami - k018701@eve.u-ryukyu.ac.jp; Jun-nosuke Uchihara - juchi@mte.biglobe.ne.jp; Taeko Okudaira - taetae@k2.dion.ne.jp; Masato Masuda - mmasuda@med.u-ryukyu.ac.jp;Takehiro Matsuda - h037233@med.u-ryukyu.ac.jp; Yuetsu Tanaka - yuetsu@S4.dion.ne.jp; Kazuiku Ohshiro - kazuoo@ryukyu.ne.jp;Naoki Mori* - n-mori@med.u-ryukyu.ac.jp* Corresponding authorPublished: 09 April 2006 Received: 07 December 2005 Accepted: 09 April 2006Retrovirology 2006, 3:22 doi:10.1186/1742-4690-3-22This article is available from: http://www.retrovirology.com/content/3/1/22© 2006 Tomita et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Human T-cell leukemia virus type 1 (HTLV-1), the etiologic agent for adult T-cell leukemia (ATL), induces cytokine-independent proliferation of T-cells, associated with the acquisition of constitutive activation of Janus kinases (Jak) and signal transducers and activators of transcription (Stat) proteins. Our purposes in this study were to determine whether activation of Jak-Stat pathway is responsible for the proliferation and survival of ATL cells, and to explore mechanisms by which inhibition of Jak-Stat pathway kills ATL cells. Results: Constitutive activation of Stat3 and Stat5 was observed in HTLV-1-infected T-cell lines and primary ATL cells, but not in HTLV-1-negative T-cell lines. Using AG490, a Jak-specific inhibitor, we demonstrated that the activation of Stat3 and Stat5 was mediated by the constitutive phosphorylation of Jak proteins. AG490 inhibited the growth of HTLV-1-infected T-cell lines and primary ATL cells by inducing G1 cell-cycle arrest mediated by altering the expression of cyclin D2, Cdk4, p53, p21, Pim-1 and c-Myc, and by apoptosis mediated by the reduced expression of c-IAP2, XIAP, survivin and Bcl-2. Importantly, AG490 did not inhibit the growth of normal peripheral blood mononuclear cells. Conclusion: Our results indicate that activation of Jak-Stat pathway is responsible for the proliferation and survival of ATL cells. Inhibition of this pathway may provide a new approach for the treatment of ATL. Page 1 of 10 (page number not for citation purposes)Retrovirology 2006, 3:22 http://www.retrovirology.com/content/3/1/22 HTLV-1-transformed T-cell lines, but it fails to disrupt theBackgroundAdul ...