The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling.
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.
Staber
Philipp B
PB
Klinische Abteilung für Hämatologie, Universitätsklinik für Innere Medizin, Medizinische, Universität Graz, Auenbruggerplatz 38, A-8036 Graz, Austria. philipp.staber@meduni-graz.at
Vesely
Paul
P
Haq
Naznin
N
Ott
Rene G
RG
Funato
Kotaro
K
Bambach
Isabella
I
Fuchs
Claudia
C
Schauer
Silvia
S
Linkesch
Werner
W
Hrzenjak
Andelko
A
Dirks
Wilhelm G
WG
Sexl
Veronika
V
Bergler
Helmut
H
Kadin
Marshall E
ME
Sternberg
David W
DW
Kenner
Lukas
L
Hoefler
Gerald
G
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
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