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
|
---|---|
Published in |
Molecular Cancer, November 2013
|
DOI | 10.1186/1476-4598-12-146 |
Pubmed ID | |
Authors |
Hui Ren, Junghui Koo, Baoxiang Guan, Ping Yue, Xingming Deng, Mingwei Chen, Fadlo R Khuri, Shi-Yong Sun |
Abstract |
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. 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. API-1 induces GSK3-dependent, β-TrCP- and FBXW7-mediated Mcl-1 degradation, resulting in induction of apoptosis. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 30 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 7 | 23% |
Researcher | 6 | 20% |
Student > Bachelor | 3 | 10% |
Student > Master | 3 | 10% |
Student > Postgraduate | 2 | 7% |
Other | 3 | 10% |
Unknown | 6 | 20% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 9 | 30% |
Biochemistry, Genetics and Molecular Biology | 6 | 20% |
Medicine and Dentistry | 2 | 7% |
Chemistry | 2 | 7% |
Business, Management and Accounting | 1 | 3% |
Other | 2 | 7% |
Unknown | 8 | 27% |