Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner

被引：75

作者：

Elgendy, Mohamed ^{[1
]}

Ciro, Marco ^{[1
,2
]}

Abdel-Aziz, Amal Kamal ^{[1
]}

Belmonte, Giuseppe ^{[3
]}

Dal Zuffo, Roberto ^{[1
]}

Mercurio, Ciro ^{[1
]}

Miracco, Clelia ^{[3
]}

Lanfrancone, Luisa ^{[1
]}

Foiani, Marco ^{[2
,4
]}

Minucci, Saverio ^{[1
,4
,5
]}

机构：

[1] European Inst Oncol, Dept Expt Oncol, IEO, I-20139 Milan, Italy

[2] IFOM Fdn Ist FIRC Oncol Mol, I-20139 Milan, Italy

[3] Univ Siena, Dept Human Pathol & Oncol, I-53100 Siena, Italy

[4] Univ Milan, Dept Biosci, I-20100 Milan, Italy

[5] European Inst Oncol, Drug Dev Program, IEO, I-20139 Milan, Italy

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

关键词：

TARGETING MCL-1; PROSTATE-CANCER; MELANOMA-CELLS; APOPTOSIS; EXPRESSION; RESISTANCE; SURVIVAL; THERAPY; INHIBITION; SABUTOCLAX;

D O I：

10.1038/ncomms6637

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Mcl-1 is a unique Bcl-2 family member that plays crucial roles in apoptosis. Apoptosis-unrelated functions of Mcl-1 are however emerging, further justifying its tight regulation. Here we unravel a novel mechanism of Mcl-1 regulation mediated by the haplo-insufficient tumour suppressor Beclin 1. Beclin 1 negatively modulates Mcl-1 stability in a reciprocal manner whereby depletion of one leads to the stabilization of the other. This co-regulation is independent of autophagy and of their physical interaction. Both Beclin 1 and Mcl-1 are deubiquitinated and thus stabilized by binding to a common deubiquitinase, USP9X. Beclin 1 and Mcl-1 negatively modulate the proteasomal degradation of each other through competitive displacement of USP9X. The analysis of patient-derived melanoma cells and tissue samples shows that the levels of Beclin 1 decrease, while Mcl-1 levels subsequently increase during melanoma progression in a significant inter-dependent manner. The identified inverse co-regulation of Beclin 1 and Mcl-1 represents a mechanism of functional counteraction in cancer.

引用

页数：11

共 37 条

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