| Domaine : |
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Sciences du Vivant/Biologie cellulaire/Organisation et fonctions cellulaires
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PMID (identifiant
de la référence Pubmed) : |
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 (19693674) |
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| Titre : |
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A flavivirus protein M-derived peptide directly permeabilizes mitochondrial membranes, triggers cell death and reduces human tumor growth in nude mice. |
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| Auteur(s) : |
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Magali Brabant1, Ludwig Baux1, Richard Casimir1, 2, Jean Paul Briand2, Olivier Chaloin2, Mathieu Porceddu1, Nelly Buron1, David Chauvier1, Myriam Lassalle1, Hervé Lecoeur1, Alain Langonné1, Sylvie Dupont1, Olivier Déas1, Catherine Brenner3, Dominique Rebouillat1, Sylviane Muller2, Annie Borgne-Sanchez1, Etienne Jacotot4 |
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| Laboratoire : |
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| Résumé : |
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Dengue viruses belong to the Flavivirus family and are responsible for hemorrhagic fever in Human. Dengue virus infection triggers apoptosis especially through the expression of the small membrane (M) protein. Using isolated mitochondria, we found that synthetic peptides containing the C-terminus part of the M ectodomain caused apoptosis-related mitochondrial membrane permeabilization (MMP) events. These events include matrix swelling and the dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)). Protein M Flavivirus sequence alignments and helical wheel projections reveal a conserved distribution of charged residues. Moreover, when combined to the cell penetrating HIV-1 Tat peptide transduction domain (Tat-PTD), this sequence triggers a caspase-dependent cell death associated with DeltaPsi(m) loss and cytochrome c release. Mutational approaches coupled to functional screening on isolated mitochondria resulted in the selection of a protein M derived sequence containing nine residues with potent MMP-inducing properties on isolated mitochondria. A chimeric peptide composed of a Tat-PTD linked to the 9-mer entity triggers MMP and cell death. Finally, local administration of this chimeric peptide induces growth inhibition of xenograft prostate PC3 tumors in immuno-compromised mice, and significantly enhances animal survival. Together, these findings support the notion of using viral genomes as valuable sources to discover mitochondria-targeted sequences that may lead to the development of new anticancer compounds. |
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Langue du texte
intégral : |
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Anglais |
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| Type de publication : |
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Articles dans des revues avec comité de lecture |
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| DOI : |
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10.1007/s10495-009-0394-y |
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| Journal : |
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| Apoptosis (Apoptosis) |
| Publisher |
Springer Verlag (Germany) |
| ISSN |
1360-8185 (eISSN : 1573-675X) |
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| Audience : |
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internationale |
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| Date de publication : |
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10/2009 |
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| Volume : |
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14 |
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| Numéro : |
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10 |
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| Page, identifiant, ... : |
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1190-203 |
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