Anastasov, N. ; Bonzheim, I.* ; Rudelius, M.* ; Klier, M.* ; Dau, T. ; Angermeier, D. ; Duyster, J.* ; Pittaluga, S.* ; Fend, F.* ; Raffeld, M.* ; Quintanilla-Martinez, L.
C/EBPβ expression in ALK-positive anaplastic large cell lymphomas (ALCL) is required for cell proliferation and is induced by the STAT3 signaling pathway.
Haematologica 95, 760-767 (2010)
Background: ALK+ALCL is characterized by the t(2;5) chromosomal translocation, resulting in the expression of the fusion protein NPM-ALK. Recently, we reported the abnormal expression of the transcription factor C/EBPβ in ALK+ALCL, and demonstrated its dependence on NPM-ALK kinase activity. Design and Methods: In this study, the role of C/EBPβ in proliferation and survival of ALK+ALCL was investigated, as well as, the mechanism of its expression and activity. Highly effective shRNA sequences and/or pharmacological inhibitors were used to abrogate C/EBPβ, STAT3, AKT, ERK1/2 and mTOR expression or activity.. Results: Interference with C/EBPβ expression resulted in a dramatic decrease in cell proliferation in ALK+ALCLs, with a mild induction of apoptosis after 6 days. Downregulation of STAT3 resulted in a marked decrease in C/EBPβ mRNA and protein levels with impairment in cell proliferation and viability, underscoring the important role of these two proteins in ALK-mediated oncogenesis. Additionally, we demonstrated that reduction of ERK1/2 activity led to C/EBPβ Thr235 dephosphorylation and moderate growth retardation. The AKT/mTOR signaling pathway did not have any influence on C/EBPβ expression or C/EBPβ phosphorylation. Conclusions: These findings reveal the convergence of STAT3 and ERK1/2 signaling pathways activated by NPM-ALK, in mediating the regulation of C/EBPβ expression, a transcription factor central to NPM-ALK transformation.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Typ der Hochschulschrift
Herausgeber
Schlagwörter
Anaplastic Large Cell Lymphoma (ALCL); C/EBPβ; STAT3; RNA interference; cell proliferation; BINDING-PROTEIN-BETA; TYROSINE KINASE; GROWTH-HORMONE; MESSENGER-RNA; CYCLIN D1; TRANSCRIPTION; ACTIVATION; CANCER; TARGET; PHOSPHORYLATION
Keywords plus
Sprache
englisch
Veröffentlichungsjahr
2010
Prepublished im Jahr
2009
HGF-Berichtsjahr
2010
ISSN (print) / ISBN
0390-6078
e-ISSN
1592-8721
ISBN
Bandtitel
Konferenztitel
Konferzenzdatum
Konferenzort
Konferenzband
Quellenangaben
Band: 95,
Heft: 5,
Seiten: 760-767
Artikelnummer: ,
Supplement: ,
Reihe
Verlag
Ferrata Storti Foundation
Verlagsort
Tag d. mündl. Prüfung
0000-00-00
Betreuer
Gutachter
Prüfer
Topic
Hochschule
Hochschulort
Fakultät
Veröffentlichungsdatum
0000-00-00
Anmeldedatum
0000-00-00
Anmelder/Inhaber
weitere Inhaber
Anmeldeland
Priorität
Begutachtungsstatus
Peer reviewed
POF Topic(s)
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30202 - Environmental Health
Forschungsfeld(er)
Enabling and Novel Technologies
Radiation Sciences
PSP-Element(e)
G-500300-001
G-500200-001
Förderungen
Copyright
Erfassungsdatum
2009-12-31