Document Detail


Upregulation of the CDC25A phosphatase down-stream of the NPM/ALK oncogene participates to anaplastic large cell lymphoma enhanced proliferation.
MedLine Citation:
PMID:  19305144     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Here, we demonstrate that the expression of the dual specificity phosphatase CDC25A, a key regulator of cell cycle progression, is deregulated in Ba/F3 cells expressing the oncogenic protein NPM/ALK and in human cell lines derived from NPM/ALK-positive anaplastic large cell lymphomas (ALCL). Both transcriptional and post-translational mechanisms account for the constitutive expression of the protein, and the PI3K/Akt pathway is essential for this process. Importantly, pharmacological inhibition of CDC25 dramatically inhibits the proliferation of NPM/ALK-expressing cells, while moderately affecting the proliferation of control Ba/F3 cells. RNA interference-mediated downregulation of CDC25A confirmed that NPM/ALK-expressing cells are highly dependent on this protein for their proliferation. Moreover, similar PI3K/AKt-mediated constitutive expression of CDC25A takes place down-stream of other hematological oncogenes, including BCR/ABL in Chronic Myeloid Leukemia and FLT3-ITD in Acute Myeloid Leukemia. Altogether, our data point to the functional link between hematopoietic oncogenic tyrosine kinases and the G(1) cell cycle regulator CDC25A, and we propose that this protein may be a potential therapeutic target in ALCL and other hematological malignancies.
Authors:
Anne Fernandez-Vidal; Anne Mazars; Emilie-Fleur Gautier; Grégoire Prévost; Bernard Payrastre; Stéphane Manenti
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-05-26
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  8     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-04-22     Completed Date:  2009-06-03     Revised Date:  2011-06-08    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1373-9     Citation Subset:  IM    
Affiliation:
INSERM U563-IFR30, Centre de Physiopathologie de Toulouse-Purpan, Département Oncogenèse, signalisation et innovation thérapeutique, Université Paul Sabatier, Toulouse, France.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line, Tumor
Cell Proliferation
Humans
Lymphoma, Large-Cell, Anaplastic / enzymology*,  pathology*
Mice
Oncogene Proteins, Fusion / metabolism
Oncogenes*
Phosphatidylinositol 3-Kinases / metabolism
Protein-Tyrosine Kinases / metabolism*
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction
Up-Regulation*
cdc25 Phosphatases / metabolism*
Chemical
Reg. No./Substance:
0/Oncogene Proteins, Fusion; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.1/anaplastic lymphoma kinase; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.1.3.16/Cdc25a protein, mouse; EC 3.1.3.48/CDC25A protein, human; EC 3.1.3.48/cdc25 Phosphatases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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