Faculty Collaboration Database

NPM-ALK oncogenic kinase promotes cell-cycle progression through activation of JNK/cJun signaling in anaplastic large-cell lymphoma. Blood 2007 Sep 01;110(5):1621-30

Date

04/10/2007

Pubmed ID

17416736

DOI

10.1182/blood-2006-11-059451

Scopus ID

2-s2.0-34548821219 (requires institutional sign-in at Scopus site)   75 Citations

Abstract

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 (210K>R), 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 dephosphorylation of JNK and cJun and decreased AP-1 DNA-binding. In addition, 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 the cJun gene by siRNA led to a decreased S-phase cell-cycle fraction associated with upregulation of p21 and downregulation 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.

Author List

Leventaki V, Drakos E, Medeiros LJ, Lim MS, Elenitoba-Johnson KS, Claret FX, Rassidakis GZ

MESH terms used to index this publication - Major topics in bold

Anthracenes
Cell Cycle
Cell Transformation, Neoplastic
Chromosomes, Human, Pair 2
Chromosomes, Human, Pair 5
Cyclin A
Cyclin D3
Cyclins
Dose-Response Relationship, Drug
Down-Regulation
Enzyme Activation
Humans
Jurkat Cells
Lymphoma, Large B-Cell, Diffuse
Mitogen-Activated Protein Kinase 8
Mitogen-Activated Protein Kinase 9
Oncogene Proteins, Fusion
Phosphorylation
Protein-Tyrosine Kinases
Signal Transduction
Transcription Factor AP-1
Transcription, Genetic
Translocation, Genetic
Up-Regulation
p21-Activated Kinases