|
|
Blood, 1 September 2007, Vol. 110, No. 5, pp. 1621-1630.
Prepublished online as a Blood First Edition Paper on April 6, 2007; DOI 10.1182/blood-2006-11-059451.
 Previous Article | Next Article 
Submitted November 27, 2006
Accepted March 28, 2007
NPM-ALK oncogenic kinase promotes cell cycle progression through activation of JNK/cJun signaling in anaplastic large cell lymphoma
Vasiliki Leventaki, Elias Drakos, L. Jeffrey Medeiros, Megan S Lim, Kojo S Elenitoba-Johnson, Francois X Claret, and George Z Rassidakis*
Dept of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
Dept of Pathology, University of Michigan, Ann Arbor, MI, United States
Dept of Molecular Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: gzrassidakis{at}mdanderson.org.
Anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in aberrant expression of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). We show that, in 293T and Jurkat cells, forced expression of active NPM-ALK, but not kinase-dead mutant NPM-ALK (K210R), induced JNK and cJun phosphorylation, and this was linked to a dramatic increase in AP-1 transcriptional activity. Conversely, inhibition of ALK activity in NPM-ALK+ ALCL cells resulted in a concentration-dependent de-phosphorylation of JNK and cJun and decreased AP-1 DNA-binding. Additionally, JNK physically binds NPM-ALK and is highly activated in cultured and primary NPM-ALK+ ALCL cells. cJun phosphorylation in NPM-ALK+ ALCL cells is mediated by JNKs as shown by selective knocking down of JNK1 and JNK2 genes using siRNA. Inhibition of JNK activity using SP600125 decreased cJun phosphorylation and AP-1 transcriptional activity and this was associated with decreased cell proliferation and G2/M cell cycle arrest in a dose-dependent manner. Silencing of cJun gene by siRNA led to decreased S-phase fraction of cell cycle associated with up-regulation of p21 and down-regulation of cyclin D3 and cyclin A. Taken together, these findings reveal a novel function of NPM-ALK, phosphorylation and activation of JNK and cJun, which may contribute to uncontrolled cell cycle progression and oncogenesis.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
Y.-X. Cui, A. Kerby, F. K. E. McDuff, H. Ye, and S. D. Turner
NPM-ALK inhibits the p53 tumor suppressor pathway in an MDM2 and JNK-dependent manner
Blood,
May 21, 2009;
113(21):
5217 - 5227.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. R. Singh, J. H. Cho-Vega, Y. Davuluri, S. Ma, F. Kasbidi, C. Milito, P. A. Lennon, E. Drakos, L. J. Medeiros, R. Luthra, et al.
Sonic Hedgehog Signaling Pathway Is Activated in ALK-Positive Anaplastic Large Cell Lymphoma
Cancer Res.,
March 15, 2009;
69(6):
2550 - 2558.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Wu, P. Wang, L. C. Young, R. Lai, and L. Li
Proteome-Wide Identification of Novel Binding Partners to the Oncogenic Fusion Gene Protein, NPM-ALK, using Tandem Affinity Purification and Mass Spectrometry
Am. J. Pathol.,
February 1, 2009;
174(2):
361 - 370.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. B. Staber, P. Vesely, N. Haq, R. G. Ott, K. Funato, I. Bambach, C. Fuchs, S. Schauer, W. Linkesch, A. Hrzenjak, et al.
The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling
Blood,
November 1, 2007;
110(9):
3374 - 3383.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
