title: 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.
authors: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors: R
authors: R
authors: Palermo
authors: S
authors: S
authors: Checquolo
authors: A
authors: A
authors: Giovenco
authors: P
authors: P
authors: Grazioli
authors: V
authors: V
authors: Kumar
authors: A F
authors: AF
authors: Campese
authors: A
authors: A
authors: Giorgi
authors: M
authors: M
authors: Napolitano
authors: G
authors: G
authors: Canettieri
authors: G
authors: G
authors: Ferrara
authors: M E
authors: ME
authors: Schininà
authors: M
authors: M
authors: Maroder
authors: L
authors: L
authors: Frati
authors: A
authors: A
authors: Gulino
authors: A
authors: A
authors: Vacca
authors: I
authors: I
authors: Screpanti
mesh_terms: D000107:Acetylation; D000818:Animals; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D006801:Humans; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000209:etiology*; D008213:Lymphocyte Activation; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D054875:Ubiquitination
chemical_list: D056572:Histone Deacetylase Inhibitors; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D046988:Proteasome Endopeptidase Complex