| 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. |
| Authors | Vasiliki Leventaki, Elias Drakos, L Jeffrey Medeiros, Megan S Lim, Kojo S Elenitoba-Johnson, Francois X Claret, George Z Rassidakis
(Affiliation: Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.)
|
| Journal | Blood
(Blood)
Vol. 110
Issue 5
Pg. 1621-30
(Sep 1 2007)
ISSN: 0006-4971 United States |
| PMID | 17416736
(Publication Type: Journal Article)
|
| Chemical References |
- Anthracenes
- Cyclin A
- Cyclins
- Oncogene Proteins, Fusion
- Transcription Factor AP-1
- anthra(1,9-cd)pyrazol-6(2H)-one
- cyclin D3
- p80(NPM-ALK) protein
- Protein-Tyrosine Kinases
- Mitogen-Activated Protein Kinase 8
- Mitogen-Activated Protein Kinase 9
- Protein-Serine-Threonine Kinases
- p21-Activated Kinases
|
| Topics |
- Anthracenes
(pharmacology, therapeutic use)
- Cell Cycle
(drug effects, genetics)
- Cell Transformation, Neoplastic
(genetics, metabolism)
- Chromosomes, Human, Pair 2
(genetics, metabolism)
- Chromosomes, Human, Pair 5
(genetics, metabolism)
- Cyclin A
(biosynthesis, genetics)
- Cyclins
(biosynthesis, genetics)
- Dose-Response Relationship, Drug
- Down-Regulation
(drug effects, genetics)
- Enzyme Activation
(drug effects, genetics)
- Humans
- Jurkat Cells
- Lymphoma, Large B-Cell, Diffuse
(drug therapy, enzymology, genetics)
- Mitogen-Activated Protein Kinase 8
(antagonists & inhibitors, genetics, metabolism)
- Mitogen-Activated Protein Kinase 9
(antagonists & inhibitors, genetics, metabolism)
- Oncogene Proteins, Fusion
(genetics, metabolism)
- Phosphorylation
(drug effects)
- Protein-Serine-Threonine Kinases
(biosynthesis, genetics)
- Protein-Tyrosine Kinases
(genetics, metabolism)
- Signal Transduction
(drug effects, genetics)
- Transcription Factor AP-1
(genetics, metabolism)
- Transcription, Genetic
(drug effects, genetics)
- Translocation, Genetic
(drug effects, genetics)
- Up-Regulation
(drug effects, genetics)
- p21-Activated Kinases
|
