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Blood, 1 November 2007, Vol. 110, No. 9, pp. 3374-3383. Prepublished online as a Blood First Edition Paper on August 9, 2007; DOI 10.1182/blood-2007-02-071258. This Article Full Text Full Text (PDF) Supplemental Methods, Table, and Figures All Versions of this Article: blood-2007-02-071258v1 110/9/3374    most recent 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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Staber, P. B. Articles by Hoefler, G. Search for Related Content PubMed PubMed Citation Articles by Staber, P. B. Articles by Hoefler, G. Related Collections Neoplasia Signal Transduction Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling Philipp B. Staber1, Paul Vesely2, Naznin Haq3, Rene G. Ott4, Kotaro Funato3, Isabella Bambach1, Claudia Fuchs1,2, Silvia Schauer2, Werner Linkesch1, Andelko Hrzenjak2, Wilhelm G. Dirks5, Veronika Sexl4, Helmut Bergler6, Marshall E. Kadin7,8, David W. Sternberg3, Lukas Kenner9,10, and Gerald Hoefler2 1 Klinische Abteilung für Hämatologie, Universitätsklinik für Innere Medizin, Medizinische, Universität Graz, Graz, Austria; 2 Institut für Pathologie, Medizinische Universität Graz, Graz, Austria; 3 Mount Sinai School of Medicine, New York, NY; 4 Institut für Pharmakologie, Universität Wien, Wien, Austria; 5 Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ), Braunschweig, Germany; 6 Institut für Molekulare Biowissenschaften, Karl-Franzens Universität Graz, Graz, Austria; 7 Department of Dermatology, Brigham and Women's Hospital, Boston, MA; 8 Roger Williams Medical Center, Providence, RI; 9 Institut für Pathologie, Medizinische Universität Wien, Wien, Austria; 10 Boltzmann Institute for Cancer Research, Vienna, Austria Anaplastic large cell lymphomas (ALCLs) are highly proliferating tumors that commonly express the AP-1 transcription factor JunB. ALK fusions occur in approximately 50% of ALCLs, and among these, 80% have the t(2;5) translocation with NPM-ALK expression. We report greater activity of JunB in NPM-ALK–positive than in NPM-ALK–negative ALCLs. Specific knockdown of JUNB mRNA using small interfering RNA and small hairpin RNA in NPM-ALK–expressing cells decreases cellular proliferation as evidenced by a reduced cell count in the G2/M phase of the cell cycle. Expression of NPM-ALK results in ERK1/2 activation and transcriptional up-regulation of JUNB. Both NPM-ALK–positive and –negative ALCL tumors demonstrate active ERK1/2 signaling. In contrast to NPM-ALK–negative ALCL, the mTOR pathway is active in NPM-ALK–positive lymphomas. Pharmacological inhibition of mTOR in NPM-ALK–positive cells down-regulates JunB protein levels by shifting JUNB mRNA translation from large polysomes to monosomes and ribonucleic particles (RNPs), and decreases cellular proliferation. Thus, JunB is a critical target of mTOR and is translationally regulated in NPM-ALK–positive lymphomas. This is the first study demonstrating translational control of AP-1 transcription factors in human neoplasia. In conjunction with NPM-ALK, JunB enhances cell cycle progression and may therefore represent a therapeutic target. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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