Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
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.
The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling.
Blood. 2007; 110(9):3374-3383
Doi: 10.1182/blood-2007-02-071258
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- Führende Autor*innen der Med Uni Graz
- Staber Philipp
- Vesely Paul
- Co-Autor*innen der Med Uni Graz
- Fuchs Claudia
- Höfler Gerald
- Hrzenjak Andelko
- Kenner Lukas
- Linkesch Werner
- Perchthaler Isabella
- Schauer Silvia
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Catalytic Domain - physiology
- Gene Expression Profiling -
- Gene Expression Regulation, Neoplastic -
- Humans -
- 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 -