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.

Acetylation controls Notch3 stability and function in T-cell leukemia / Palermo, Rocco; Checquolo, Saula; A., Giovenco; Grazioli, Paola; Kumar, Vivek; Campese, Antonio Francesco; Giorgi, Alessandra; Napolitano, Maddalena; Canettieri, Gianluca; G., Ferrara; Schinina', Maria Eugenia; Maroder, Marella; Frati, Luigi; Gulino, Alberto; Vacca, Alessandra; Screpanti, Isabella. - In: ONCOGENE. - ISSN 0950-9232. - STAMPA. - 31:33(2012), pp. 3807-3817. [10.1038/onc.2011.533]

Acetylation controls Notch3 stability and function in T-cell leukemia

PALERMO, ROCCO;CHECQUOLO, Saula;GRAZIOLI, PAOLA;KUMAR, vivek;CAMPESE, Antonio Francesco;GIORGI, ALESSANDRA;NAPOLITANO, Maddalena;CANETTIERI, Gianluca;SCHININA', Maria Eugenia;MARODER, Marella;FRATI, Luigi;GULINO, Alberto;VACCA, Alessandra;SCREPANTI, Isabella
2012

Abstract

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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/434259
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