An RNAi Screen Identifies TRRAP as a Regulator of Brain Tumor-Initiating Cell Differentiation

被引：98

作者：

Wurdak, Heiko ^{[1
,2
]}

Zhu, Shoutian ^{[1
,2
]}

Romero, Angelica ^{[3
]}

Lorger, Mihaela ^{[4
]}

Watson, James ^{[3
]}

Chiang, Chih-yuan ^{[3
]}

Zhang, Jay ^{[3
]}

Natu, Vanita S. ^{[5
]}

Lairson, Luke L. ^{[1
,2
]}

Walker, John R. ^{[3
]}

Trussell, Christopher M. ^{[3
]}

Harsh, Griffith R. ^{[5
]}

Vogels, Hannes ^{[6
]}

Felding-Habermann, Brunhilde ^{[4
]}

Orth, Anthony P. ^{[3
]}

Miraglia, Loren J. ^{[3
]}

Rines, Daniel R. ^{[3
]}

Skirboll, Stephen L. ^{[5
,7
]}

Schultz, Peter G. ^{[1
,2
,3
]}

机构：

[1] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

[2] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA

[3] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

[4] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA

[5] Stanford Univ, Dept Neurosurg, Med Ctr, Stanford, CA 94305 USA

[6] Stanford Univ, Neuropathol Lab, Med Ctr, Dept Pathol, Stanford, CA 94305 USA

[7] VA Palo Alto Hlth Care Syst, Sect Neurosurg, Palo Alto, CA 94304 USA

来源：

CELL STEM CELL | 2010年 / 6卷 / 01期

关键词：

CANCER STEM-CELL; GLIOBLASTOMA-MULTIFORME; COFACTOR TRRAP; SELF-RENEWAL; C-MYC; EXPRESSION; LINES; ACETYLATION; DERIVATION; APOPTOSIS;

D O I：

10.1016/j.stem.2009.11.002

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer associated with a very poor prognosis. Recently, the initiation and growth of GBM has been linked to brain tumor-initiating cells (BTICs), which are poorly differentiated and share features with neural stem cells (NSCs). Here we describe a kinome-wide RNA interference screen to identify factors that control the tumorigenicity of BTICs. We identified several genes whose silencing induces differentiation of BTICs derived from multiple GBM patients. In particular, knockdown of the adaptor protein TRRAP significantly increased differentiation of cultured BTICs, sensitized the cells to apoptotic stimuli, and negatively affected cell cycle progression. TRRAP knockdown also significantly suppressed tumor formation upon intracranial BTIC implantation into mice. Together, these findings support a critical role for TRRAP in maintaining a tumorigenic, stem cell-like state.

引用

页码：37 / 47

页数：11

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