The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia

Recent studies have shown that activating mutations of NOTCH1 are responsible for the majority of T cell acute lymphoblastic leukemia (T-ALL) cases. Most of these mutations truncate its C-terminal domain, a region that is important for the NOTCH1 proteasome-mediated degradation. We report that the E...

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Main Authors:	Thompson, Benjamin J., Buonamici, Silvia, Sulis, Maria Luisa, Palomero, Teresa, Vilimas, Tomas, Basso, Giuseppe, Ferrando, Adolfo, Aifantis, Iannis
Format:	Online
Language:	English
Published:	The Rockefeller University Press 2007
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118676/

id	pubmed-2118676
recordtype	oai_dc
spelling	pubmed-21186762008-02-06 The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia Thompson, Benjamin J. Buonamici, Silvia Sulis, Maria Luisa Palomero, Teresa Vilimas, Tomas Basso, Giuseppe Ferrando, Adolfo Aifantis, Iannis Articles Recent studies have shown that activating mutations of NOTCH1 are responsible for the majority of T cell acute lymphoblastic leukemia (T-ALL) cases. Most of these mutations truncate its C-terminal domain, a region that is important for the NOTCH1 proteasome-mediated degradation. We report that the E3 ligase FBW7 targets NOTCH1 for ubiquitination and degradation. Our studies map in detail the amino acid degron sequence required for NOTCH1–FBW7 interaction. Furthermore, we identify inactivating FBW7 mutations in a large fraction of human T-ALL lines and primary leukemias. These mutations abrogate the binding of FBW7 not only to NOTCH1 but also to the two other characterized targets, c-Myc and cyclin E. The majority of the FBW7 mutations were present during relapse, and they were associated with NOTCH1 HD mutations. Interestingly, most of the T-ALL lines harboring FBW7 mutations were resistant to γ-secretase inhibitor treatment and this resistance appeared to be related to the stabilization of the c-Myc protein. Our data suggest that FBW7 is a novel tumor suppressor in T cell leukemia, and implicate the loss of FBW7 function as a potential mechanism of drug resistance in T-ALL. The Rockefeller University Press 2007-08-06 /pmc/articles/PMC2118676/ /pubmed/17646408 http://dx.doi.org/10.1084/jem.20070872 Text en Copyright © 2007, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Thompson, Benjamin J. Buonamici, Silvia Sulis, Maria Luisa Palomero, Teresa Vilimas, Tomas Basso, Giuseppe Ferrando, Adolfo Aifantis, Iannis
spellingShingle	Thompson, Benjamin J. Buonamici, Silvia Sulis, Maria Luisa Palomero, Teresa Vilimas, Tomas Basso, Giuseppe Ferrando, Adolfo Aifantis, Iannis The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia
author_facet	Thompson, Benjamin J. Buonamici, Silvia Sulis, Maria Luisa Palomero, Teresa Vilimas, Tomas Basso, Giuseppe Ferrando, Adolfo Aifantis, Iannis
author_sort	Thompson, Benjamin J.
title	The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia
title_short	The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia
title_full	The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia
title_fullStr	The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia
title_full_unstemmed	The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia
title_sort	scffbw7 ubiquitin ligase complex as a tumor suppressor in t cell leukemia
description	Recent studies have shown that activating mutations of NOTCH1 are responsible for the majority of T cell acute lymphoblastic leukemia (T-ALL) cases. Most of these mutations truncate its C-terminal domain, a region that is important for the NOTCH1 proteasome-mediated degradation. We report that the E3 ligase FBW7 targets NOTCH1 for ubiquitination and degradation. Our studies map in detail the amino acid degron sequence required for NOTCH1–FBW7 interaction. Furthermore, we identify inactivating FBW7 mutations in a large fraction of human T-ALL lines and primary leukemias. These mutations abrogate the binding of FBW7 not only to NOTCH1 but also to the two other characterized targets, c-Myc and cyclin E. The majority of the FBW7 mutations were present during relapse, and they were associated with NOTCH1 HD mutations. Interestingly, most of the T-ALL lines harboring FBW7 mutations were resistant to γ-secretase inhibitor treatment and this resistance appeared to be related to the stabilization of the c-Myc protein. Our data suggest that FBW7 is a novel tumor suppressor in T cell leukemia, and implicate the loss of FBW7 function as a potential mechanism of drug resistance in T-ALL.
publisher	The Rockefeller University Press
publishDate	2007
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118676/
_version_	1611414901707767808

The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia

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