DEPTOR Is an mTOR Inhibitor Frequently Overexpressed in Multiple Myeloma Cells and Required for Their Survival

被引：1005

作者：

Peterson, Timothy R. ^{[1
,2
]}

Laplante, Mathieu ^{[1
,2
]}

Thoreen, Carson C. ^{[1
,2
]}

Sancak, Yasemin ^{[1
,2
]}

Kang, Seong A. ^{[1
,2
]}

Kuehl, W. Michael ^{[4
]}

Gray, Nathanael S. ^{[5
,6
]}

Sabatini, David M. ^{[1
,2
,3
]}

机构：

[1] Nine Cambridge Ctr, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[2] MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA 02139 USA

[3] MIT, Koch Ctr Integrat Canc Res, Cambridge, MA 02139 USA

[4] NCI, Bethesda, MD 20814 USA

[5] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

来源：

CELL | 2009年 / 137卷 / 05期

基金：

加拿大健康研究院; 美国国家卫生研究院;

关键词：

C-MAF; PROTEIN; PHOSPHORYLATION; KINASE; COMPLEX; DYSREGULATION; PROLIFERATION; ACTIVATION; DOMAINS; TARGET;

D O I：

10.1016/j.cell.2009.03.046

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：

The mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR as an mTOR-interacting protein whose expression is negatively regulated by mTORC1 and mTORC2. Loss of DEPTOR activates S6K1, Akt, and SGK1, promotes cell growth and survival, and activates mTORC1 and mTORC2 kinase activities. DEPTOR overexpression suppresses S6K1 but, by relieving feedback inhibition from mTORC1 to PI3K signaling, activates Akt. Consistent with many human cancers having activated mTORC1 and mTORC2 pathways, DEPTOR expression is low in most cancers. Surprisingly, DEPTOR is highly overexpressed in a subset of multiple myelomas harboring cyclin D1/D3 or c-MAF/MAFB translocations. In these cells, high DEPTOR expression is necessary to maintain PI3K and Akt activation and a reduction in DEPTOR levels leads to apoptosis. Thus, we identify a novel MTOR-interacting protein whose deregulated overexpression in multiple myeloma cells represents a mechanism for activating PI3K/Akt signaling and promoting cell survival.

引用

页码：873 / 886

页数：14

共 47 条

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