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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1621-1630. Prepublished online as a Blood First Edition Paper on April 6, 2007; DOI 10.1182/blood-2006-11-059451. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-11-059451v1 110/5/1621    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Leventaki, V. Articles by Rassidakis, G. Z. Search for Related Content PubMed PubMed Citation Articles by Leventaki, V. Articles by Rassidakis, G. Z. Related Collections Cell Cycle Oncogenes and Tumor Suppressors Signal Transduction Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA NPM-ALK oncogenic kinase promotes cell-cycle progression through activation of JNK/cJun signaling in anaplastic large-cell lymphoma Vasiliki Leventaki1, Elias Drakos1, L. Jeffrey Medeiros1, Megan S. Lim3, Kojo S. Elenitoba-Johnson3, Francois X. Claret2, and George Z. Rassidakis1 1 Department of Hematopathology, 2 Department of Molecular Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston; 3 Department of Pathology, University of Michigan, Ann Arbor Anaplastic large-cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35), resulting in aberrant expression of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). We show that in 293T and Jurkat cells, forced expression of active NPM-ALK, but not kinase-dead mutant NPM-ALK (210K>R), induced JNK and cJun phosphorylation, and this was linked to a dramatic increase in AP-1 transcriptional activity. Conversely, inhibition of ALK activity in NPM-ALK+ ALCL cells resulted in a concentration-dependent dephosphorylation of JNK and cJun and decreased AP-1 DNA-binding. In addition, JNK physically binds NPM-ALK and is highly activated in cultured and primary NPM-ALK+ ALCL cells. cJun phosphorylation in NPM-ALK+ ALCL cells is mediated by JNKs, as shown by selective knocking down of JNK1 and JNK2 genes using siRNA. Inhibition of JNK activity using SP600125 decreased cJun phosphorylation and AP-1 transcriptional activity and this was associated with decreased cell proliferation and G2/M cell-cycle arrest in a dose-dependent manner. Silencing of the cJun gene by siRNA led to a decreased S-phase cell-cycle fraction associated with upregulation of p21 and downregulation of cyclin D3 and cyclin A. Taken together, these findings reveal a novel function of NPM-ALK, phosphorylation and activation of JNK and cJun, which may contribute to uncontrolled cell-cycle progression and oncogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. B. Staber, P. Vesely, N. Haq, R. G. Ott, K. Funato, I. Bambach, C. Fuchs, S. Schauer, W. Linkesch, A. Hrzenjak, et al. The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling Blood, November 1, 2007; 110(9): 3374 - 3383. [Abstract] [Full Text] [PDF]

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