Acetylation controls Notch3 stability and function in T-cell leukemia.

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.
Document type :
Journal articles
Complete list of metadatas

Cited literature [40 references]  Display  Hide  Download

https://hal-riip.archives-ouvertes.fr/pasteur-00947754
Contributor : Istituto Pasteur Fondazione Cenci Bolognetti <>
Submitted on : Monday, February 17, 2014 - 1:06:39 PM
Last modification on : Tuesday, April 30, 2019 - 2:34:02 PM
Long-term archiving on : Sunday, April 9, 2017 - 12:18:14 PM

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document

Identifiers

Collections

Citation

R. Palermo, S. Checquolo, A. Giovenco, P. Grazioli, V. Kumar, et al.. Acetylation controls Notch3 stability and function in T-cell leukemia.. Oncogene, Nature Publishing Group, 2012, 31 (33), pp.3807-17. ⟨10.1038/onc.2011.533⟩. ⟨pasteur-00947754⟩

Share

Metrics

Record views

95