Acetylation controls Notch3 stability and function in T-cell leukemia

R. Palermo, S. Checquolo, A. Giovenco, P. Grazioli, V. Kumar, A. F. Campese, A. Giorgi, M. Napolitano, G. Canettieri, G. Ferrara, M. E. Schininà, M. Maroder, L. Frati, A. Gulino, A. Vacca, I. Screpanti

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3807-3817
Number of pages11
JournalOncogene
Volume31
Issue number33
DOIs
Publication statusPublished - Aug 16 2012

Keywords

  • acetylation
  • leukemia
  • Notch3
  • T-ALL

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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