The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling
- 1 November 2007
- journal article
- Published by American Society of Hematology in Blood
- Vol. 110 (9), 3374-3383
- https://doi.org/10.1182/blood-2007-02-071258
Abstract
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.Keywords
This publication has 44 references indexed in Scilit:
- The NPM-ALK tyrosine kinase mimics TCR signalling pathways, inducing NFAT and AP-1 by RAS-dependent mechanismsCellular Signalling, 2007
- AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cellsOncogene, 2006
- The Expression of CD30 in Anaplastic Large Cell Lymphoma Is Regulated by Nucleophosmin-Anaplastic Lymphoma Kinase–Mediated JunB Level in a Cell Type–Specific MannerCancer Research, 2006
- The Akt-mTOR tango and its relevance to cancerCancer Cell, 2005
- Common alterations in gene expression and increased proliferation in recurrent acute myeloid leukemiaOncogene, 2004
- Design and Evaluation of Chemically Synthesized siRNA Targeting the NPM-ALK Fusion Site in Anaplastic Large Cell Lymphoma (ALCL)Oligonucleotides, 2003
- AP-1 as a regulator of cell life and deathNature, 2002
- Complex Functions of AP-1 Transcription Factors in Differentiation and Survival of PC12 CellsMolecular and Cellular Biology, 2001
- Fusion of a Kinase Gene, ALK , to a Nucleolar Protein Gene, NPM , in Non-Hodgkin's LymphomaScience, 1994
- Dicistronic transcription units for gene expression in mammalian cellsGene, 1993