title: The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling.
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.
authors: Klinische Abteilung für Hämatologie, Universitätsklinik für Innere Medizin, Medizinische, Universität Graz, Auenbruggerplatz 38, A-8036 Graz, Austria. philipp.staber@meduni-graz.at
authors: Philipp B
authors: PB
authors: Staber
authors: Paul
authors: P
authors: Vesely
authors: Naznin
authors: N
authors: Haq
authors: Rene G
authors: RG
authors: Ott
authors: Kotaro
authors: K
authors: Funato
authors: Isabella
authors: I
authors: Bambach
authors: Claudia
authors: C
authors: Fuchs
authors: Silvia
authors: S
authors: Schauer
authors: Werner
authors: W
authors: Linkesch
authors: Andelko
authors: A
authors: Hrzenjak
authors: Wilhelm G
authors: WG
authors: Dirks
authors: Veronika
authors: V
authors: Sexl
authors: Helmut
authors: H
authors: Bergler
authors: Marshall E
authors: ME
authors: Kadin
authors: David W
authors: DW
authors: Sternberg
authors: Lukas
authors: L
authors: Kenner
authors: Gerald
authors: G
authors: Hoefler
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D020134:Catalytic Domain / Q000502:physiology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D011494:Protein Kinases; C107023:p80(NPM-ALK) protein; C546842:MTOR protein, human; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3