Mcl-1 Ubiquitination and Destruction

Mcl-1 Ubiquitination and Destruction

Loss of the Fbw7 tumor suppressor is common in diverse human cancer types, including T-Cell Acute Lymphoblastic Leukemia (T-ALL), although the mechanistic basis of its anti-oncogenic activity remains largely unclear. We recently reported that SCFFbw7 regulates cellular apoptosis by controlling the u...

Full description

Bibliographic Details
Main Authors: Inuzuka, Hiroyuki, Fukushima, Hidefumi, Shaik, Shavali, Liu, Pengda, Lau, Alan W., Wei, Wenyi
Format: Online
Language:English
Published: Impact Journals LLC 2011
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260810/
id pubmed-3260810
recordtype oai_dc
spelling pubmed-32608102012-01-18 Mcl-1 Ubiquitination and Destruction Inuzuka, Hiroyuki Fukushima, Hidefumi Shaik, Shavali Liu, Pengda Lau, Alan W. Wei, Wenyi Research Perspectives Loss of the Fbw7 tumor suppressor is common in diverse human cancer types, including T-Cell Acute Lymphoblastic Leukemia (T-ALL), although the mechanistic basis of its anti-oncogenic activity remains largely unclear. We recently reported that SCFFbw7 regulates cellular apoptosis by controlling the ubiquitination and destruction of the pro-survival protein, Mcl-1, in a GSK3 phosphorylation-dependent manner. We found that human T-ALL cell lines displayed a close relationship between Fbw7 loss and Mcl-1 overexpression. More interestingly, T-ALL cell lines that are deficient in Fbw7 are particularly sensitive to sorafenib, a multi-kinase inhibitor that has been demonstrated to reduce Mcl-1 expression through an unknown mechanism. On the other hand, Fbw7-deficient T-ALL cell lines are much more resistant to the Bcl-2 antagonist, ABT-737. Furthermore, reconstitution of Fbw7 or depletion of Mcl-1 in Fbw7-deficient cells restores ABT-737 sensitivity, suggesting that elevated Mcl-1 expression is important for Fbw7-deficient cells to evade apoptosis. Therefore, our work provides a novel molecular mechanism for the tumor suppression function of Fbw7. Furthermore, it provides the rationale for targeted usage of Mcl-1 antagonists to treat Fbw7-deficient T-ALL patients. Impact Journals LLC 2011-03-19 /pmc/articles/PMC3260810/ /pubmed/21608150 Text en Copyright: © 2011 Inuzuka et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
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 Inuzuka, Hiroyuki
Fukushima, Hidefumi
Shaik, Shavali
Liu, Pengda
Lau, Alan W.
Wei, Wenyi
spellingShingle Inuzuka, Hiroyuki
Fukushima, Hidefumi
Shaik, Shavali
Liu, Pengda
Lau, Alan W.
Wei, Wenyi
Mcl-1 Ubiquitination and Destruction
author_facet Inuzuka, Hiroyuki
Fukushima, Hidefumi
Shaik, Shavali
Liu, Pengda
Lau, Alan W.
Wei, Wenyi
author_sort Inuzuka, Hiroyuki
title Mcl-1 Ubiquitination and Destruction
title_short Mcl-1 Ubiquitination and Destruction
title_full Mcl-1 Ubiquitination and Destruction
title_fullStr Mcl-1 Ubiquitination and Destruction
title_full_unstemmed Mcl-1 Ubiquitination and Destruction
title_sort mcl-1 ubiquitination and destruction
description Loss of the Fbw7 tumor suppressor is common in diverse human cancer types, including T-Cell Acute Lymphoblastic Leukemia (T-ALL), although the mechanistic basis of its anti-oncogenic activity remains largely unclear. We recently reported that SCFFbw7 regulates cellular apoptosis by controlling the ubiquitination and destruction of the pro-survival protein, Mcl-1, in a GSK3 phosphorylation-dependent manner. We found that human T-ALL cell lines displayed a close relationship between Fbw7 loss and Mcl-1 overexpression. More interestingly, T-ALL cell lines that are deficient in Fbw7 are particularly sensitive to sorafenib, a multi-kinase inhibitor that has been demonstrated to reduce Mcl-1 expression through an unknown mechanism. On the other hand, Fbw7-deficient T-ALL cell lines are much more resistant to the Bcl-2 antagonist, ABT-737. Furthermore, reconstitution of Fbw7 or depletion of Mcl-1 in Fbw7-deficient cells restores ABT-737 sensitivity, suggesting that elevated Mcl-1 expression is important for Fbw7-deficient cells to evade apoptosis. Therefore, our work provides a novel molecular mechanism for the tumor suppression function of Fbw7. Furthermore, it provides the rationale for targeted usage of Mcl-1 antagonists to treat Fbw7-deficient T-ALL patients.
publisher Impact Journals LLC
publishDate 2011
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260810/
_version_ 1611500618658086912

Similar Items