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Type of publication: Journal Article
Type of document: Full Paper

Year: 2007

Authors: Staber, PB; Vesely, P; Haq, N; Ott, RG; Funato, K; Bambach, I; Fuchs, C; Schauer, S; Linkesch, W; Hrzenjak, A; Dirks, WG; Sexl, V; Bergler, H; Kadin, ME; Sternberg, DW; Kenner, L; Hoefler, G

Title: The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling.

Source: Blood. 2007; 110(9):3374-3383

Authors Vetmeduni Vienna:

Kenner Lukas
Sexl Veronika

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 Pubmed: Catalytic Domain/physiology
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Lymphoma, Large-Cell, Anaplastic/genetics*
Mitogen-Activated Protein Kinase 1/metabolism*
Mitogen-Activated Protein Kinase 3/metabolism*
Oligonucleotide Array Sequence Analysis
Protein Binding
Protein Biosynthesis
Protein Kinases/physiology*
Protein-Tyrosine Kinases/chemistry
Protein-Tyrosine Kinases/physiology*
Proto-Oncogene Proteins c-jun/genetics*
Proto-Oncogene Proteins c-jun/metabolism*
RNA, Messenger/metabolism
Receptor Protein-Tyrosine Kinases
Signal Transduction/physiology
TOR Serine-Threonine Kinases
Transcription Factor AP-1/genetics
Transcription Factor AP-1/metabolism
Transcription Factor AP-1/physiology
Transcriptional Activation*
Tumor Cells, Cultured

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