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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.
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