USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma

被引：342

作者：

Eichhorn, Pieter J. A.

Rodon, Laura

Gonzalez-Junca, Alba

Dirac, Annette ^{[2
,3
]}

Gili, Maguei

Martinez-Saez, Elena ^{[4
]}

Aura, Claudia

Barba, Ignasi ^{[4
]}

Peg, Vicente ^{[4
]}

Prat, Aleix ^{[5
]}

Cuartas, Isabel

Jimenez, Jose

Garcia-Dorado, David ^{[4
]}

Sahuquillo, Juan ^{[4
]}

Bernards, Rene ^{[2
,3
]}

Baselga, Jose ^{[6
,7
]}

Seoane, Joan ^{[1
,6
,8
]}

机构：

[1] Vall dHebron Univ Hosp, VHIO, Barcelona, Spain

[2] Netherlands Canc Inst, Div Mol Carcinogenesis, Amsterdam, Netherlands

[3] Netherlands Canc Inst, Ctr Biomed Genet, Amsterdam, Netherlands

[4] Vall dHebron Univ Hosp, VHIR, Barcelona, Spain

[5] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[6] Univ Autonoma Barcelona, Cerdanyola Del Valless, Spain

[7] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA

[8] ICREA, Barcelona, Spain

来源：

NATURE MEDICINE | 2012年 / 18卷 / 03期

基金：

欧洲研究理事会;

关键词：

E3 UBIQUITIN LIGASE; GROWTH-FACTOR-BETA; GLIOMA; SMURF2; DEGRADATION; PATHWAY; SMAD7; GENETICS; TARGETS; BIOLOGY;

D O I：

10.1038/nm.2619

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In advanced cancer, including glioblastoma, the transforming growth factor beta (TGF-beta) pathway acts as an oncogenic factor and is considered to be a therapeutic target. Using a functional RNAi screen, we identified the deubiquitinating enzyme ubiquitin-specific peptidase 15 (USP15) as a key component of the TGF-beta signaling pathway. USP15 binds to the SMAD7-SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) complex and deubiquitinates and stabilizes type I TGF-beta receptor (T beta R-I), leading to an enhanced TGF-beta signal. High expression of USP15 correlates with high TGF-beta activity, and the USP15 gene is found amplified in glioblastoma, breast and ovarian cancer. USP15 amplification confers poor prognosis in individuals with glioblastoma. Downregulation or inhibition of USP15 in a patient-derived orthotopic mouse model of glioblastoma decreases TGF-beta activity. Moreover, depletion of USP15 decreases the oncogenic capacity of patient-derived glioma-initiating cells due to the repression of TGF-beta signaling. Our results show that USP15 regulates the TGF-beta pathway and is a key factor in glioblastoma pathogenesis.

引用

页码：429 / U192

页数：8

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