Actualités
Prix et distinctions
Dr. AMATORE Christian
Professeurs invités
RAZAKA
mada
BONELLA Sara
Physics department, University Rome 1 "La Sapienza"
MIRKIN Michael
Queens College - Department of chemistry and Biochemistry - New York - USA
Dernière publication
Bousquet, David, Coudert François-Xavier, Fossati Alexandre G. J., Neimark Alexander V., Fuchs Alain H., and Boutin Anne
The Journal of Chemical Physics,
Volume 138,
p. 174706,
2013
Soutenance à venir
HDR
Mme GUILLE COLLIGNON Manon
Jeudi 6 Juin 2013 10:00
E012 (ENS, département de Chimie)
Accueil Publications Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia
Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia
| Titre | Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia |
| Type de publication | Journal Article |
| Nouvelles publications | 2009 |
| Auteurs | Tamburini, J, Green AS, Bardet V, Chapuis N, Park S, Willems L, Uzunov M, Ifrah N, Dreyfus F, Lacombe C, Mayeux P, Bouscary D |
| Journal | Blood |
| Volume | 114 |
| Fascicule | 8 |
| Pagination | 1618-1627 |
| Année de publication | Aug |
| Numéro | 0006-4971 |
| Accession Number | ISI:000269380300023 |
| Résumé | The deregulation of translation markedly contributes to the malignant phenotype in cancers, and the assembly of the translation initiating complex eIF4F is the limiting step of this process. The mammalian Target of Rapamycin Complex 1 (mTORC1) is thought to positively regulate eIF4F assembly and subsequent oncogenic protein synthesis through 4E-BP1 phosphorylation. We showed here that the translation inhibitor 4EGI-1 decreased the clonogenic growth of leukemic progenitors and induced apoptosis of blast cells, with limited toxicity against normal hematopoiesis, which emphasize the importance of translation deregulation in acute myeloid leukemia (AML) biology. However, the mTORC1 inhibitor RAD001 (a rapamycin derivate) did not induce AML blast cell apoptosis. We herein demonstrated that mTORC1 disruption using raptor siRNA or RAD001 failed to inhibit 4E-BP1 phosphorylation in AML. Moreover, RAD001 failed to inhibit eIF4F assembly, to decrease the proportion of polysome-bound c-Myc mRNA, and to reduce the translation-dependent accumulation of oncogenic proteins. We identified the Pim-2 serine/threonine kinase as mainly responsible for 4E-BP1 phosphorylation on the S-65 residue and subsequent translation control in AML. Our results strongly implicate an mTORC1-independent deregulation of oncogenic proteins synthesis in human myeloid leukemogenesis. Direct inhibition of the translation initiating complex thus represents an attractive option for the development of new therapies in AML. (Blood. 2009; 114: 1618-1627) |
| URL | <Go to ISI>://000269380300023 |
| DOI | 10.1182/blood-2008-10-184515 |
| Importer un fichier | Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia |