Acetylation controls Notch3 stability and function in T-cell leukemia
| Autor: | Paola Grazioli, Maria Eugenia Schininà, G Ferrara, Isabella Screpanti, Rocco Palermo, Saula Checquolo, Alessandra Giorgi, Vinod Kumar, Luigi Frati, Alberto Gulino, A Giovenco, Gianluca Canettieri, Maddalena Napolitano, Marella Maroder, Alessandra Vacca, Antonio Francesco Campese |
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| Přispěvatelé: | Department of Experimental Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Department of Biotechnology and Medical-Surgical Sciences, Department of Molecular Medicine, Department of Biochemical Sciences 'Rossi Fanelli', Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], RCCS OASI, Istituto Neurologico Mediterraneo (NEUROMED I.R.C.C.S.), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Università degli studi di Napoli Federico II, This work was supported by the Italian Association for Cancer Research (AIRC), the Italian Ministry of University and Research (MIUR), PRIN and FIRB Programs, the Italian Ministry of Health, the European Union (NotchIT ITN Project, FP7-MC-ITN 215761), Eleonora Lorillard Spencer Cenci Foundation and the Fondazione Roma (fellowship to RP). |
| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
T-Lymphocytes T-cell leukemia Mutant Lymphocyte Activation Mice 0302 clinical medicine t-all acetylation notch3 leukemia MESH: Animals MESH: Histone Deacetylase Inhibitors Receptor Notch3 0303 health sciences Receptors Notch MESH: Proteasome Endopeptidase Complex Acetylation Cell biology Leukemia Biochemistry 030220 oncology & carcinogenesis MESH: HEK293 Cells MESH: Acetylation MESH: Leukemia T-Cell Cell signaling Proteasome Endopeptidase Complex Leukemia T-Cell Transgene Notch signaling pathway [SDV.CAN]Life Sciences [q-bio]/Cancer Biology 03 medical and health sciences Genetics medicine Animals Humans MESH: Lymphocyte Activation Molecular Biology MESH: Mice 030304 developmental biology MESH: Humans Ubiquitination medicine.disease HDAC1 Histone Deacetylase Inhibitors MESH: T-Lymphocytes HEK293 Cells MESH: Ubiquitination MESH: Receptors Notch |
| Zdroj: | Oncogene Oncogene, Nature Publishing Group, 2012, 31 (33), pp.3807-17. ⟨10.1038/onc.2011.533⟩ |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2011.533⟩ |
| Popis: | International audience; Post-translational modifications of Notch3 and their functional role with respect to Notch3 overexpression in T-cell leukemia are still poorly understood. We identify here a specific novel property of Notch3 that is acetylated and deacetylated at lysines 1692 and 1731 by p300 and HDAC1, respectively, a balance impaired by HDAC inhibitors (HDACi) that favor hyperacetylation. By using HDACi and a non-acetylatable Notch3 mutant carrying K/R(1692-1731) mutations in the intracellular domain, we show that Notch3 acetylation primes ubiquitination and proteasomal-mediated degradation of the protein. As a consequence, Notch3 protein expression and its transcriptional activity are decreased both in vitro and in vivo in Notch3 transgenic (tg) mice, thus impairing downstream signaling upon target genes. Consistently, Notch3-induced T-cell proliferation is inhibited by HDACi, whereas it is enhanced by the non-acetylatable Notch3-K/R(1692-1731) mutant. Finally, HDACi-induced Notch3 hyperacetylation prevents in vivo growth of T-cell leukemia/lymphoma in Notch3 tg mice. Together, our findings suggest a novel level of Notch signaling control in which Notch3 acetylation/deacetylation process represents a key regulatory switch, thus representing a suitable druggable target for Notch3-sustained T-cell acute lymphoblastic leukemia therapy. |
| Databáze: | OpenAIRE |
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