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Molecular Cancer

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Open Access 01-12-2013 | Research

The E3 ubiquitin ligases β-TrCP and FBXW7 cooperatively mediates GSK3-dependent Mcl-1 degradation induced by the Akt inhibitor API-1, resulting in apoptosis

Authors: Hui Ren, Junghui Koo, Baoxiang Guan, Ping Yue, Xingming Deng, Mingwei Chen, Fadlo R Khuri, Shi-Yong Sun

Published in: Molecular Cancer | Issue 1/2013

Abstract

Background

The novel Akt inhibitor, API-1, induces apoptosis through undefined mechanisms. The current study focuses on revealing the mechanisms by which API-1 induces apoptosis.

Results

API-1 rapidly and potently reduced the levels of Mcl-1 primarily in API-1-senstive lung cancer cell lines. Ectopic expression of Mcl-1 protected cells from induction of apoptosis by API-1. API-1 treatment decreased the half-life of Mcl-1, whereas inhibition of the proteasome with MG132 rescued Mcl-1 reduction induced by API-1. API-1 decreased Mcl-1 levels accompanied with a rapid increase in Mcl-1 phosphorylation (S159/T163). Moreover, inhibition of GSK3 inhibited Mcl-1 phosphorylation and reduction induced by API-1 and antagonized the effect of API-1 on induction of apoptosis. Knockdown of either FBXW7 or β-TrCP alone, both of which are E3 ubiquitin ligases involved in Mcl-1 degradation, only partially rescued Mcl-1 reduction induced by API-1. However, double knockdown of both E3 ubiquitin ligases enhanced the rescue of API-1-induced Mcl-1 reduction.

Conclusions

API-1 induces GSK3-dependent, β-TrCP- and FBXW7-mediated Mcl-1 degradation, resulting in induction of apoptosis.

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Title: The E3 ubiquitin ligases β-TrCP and FBXW7 cooperatively mediates GSK3-dependent Mcl-1 degradation induced by the Akt inhibitor API-1, resulting in apoptosis
Authors: Hui Ren
Junghui Koo
Baoxiang Guan
Ping Yue
Xingming Deng
Mingwei Chen
Fadlo R Khuri
Shi-Yong Sun
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: Molecular Cancer / Issue 1/2013
Electronic ISSN: 1476-4598
DOI: https://doi.org/10.1186/1476-4598-12-146

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