A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-α signaling

被引：199

作者：

Gaither, Alex ^{[1
]}

Porter, Dale ^{[1
]}

Yao, Yao ^{[1
]}

Borawski, Jason ^{[1
]}

Yang, Guang ^{[1
]}

Donovan, Jerry ^{[1
]}

Sage, David ^{[1
]}

Slisz, Joanna ^{[1
]}

Tran, Mary ^{[1
]}

Straub, Christopher ^{[1
]}

Ramsey, Tim ^{[1
]}

Iourgenko, Vadim ^{[1
]}

Huang, Alan ^{[1
]}

Chen, Yan ^{[1
]}

Schlegel, Robert ^{[1
]}

Labow, Mark ^{[1
]}

Fawell, Stephen ^{[1
]}

Sellers, William R. ^{[1
]}

Zawel, Leigh ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Oncol Dis Area & Dev & Mol Pathways, Cambridge, MA 02139 USA

来源：

CANCER RESEARCH | 2007年 / 67卷 / 24期

关键词：

D O I：

10.1158/0008-5472.CAN-07-5173

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Smac mimetic compounds targeting the inhibitor of apoptosis proteins (UP) baculoviral LAP repeat-3 domain are presumed to reduce the threshold for apoptotic cell death by alleviating caspase-9 repression. We explored this tenet in an unbiased manner by searching for small interfering RNAs that are able to confer resistance to the Smac mimetic compound LBW242. Among the screening hits were multiple components of the tumor necrosis factor alpha (TNF alpha) signaling pathway as well as X-linked inhibitor of apoptosis (XIAP) itself. Here, we show that in a subset of highly sensitive tumor cell lines, activity of LBW242 is dependent on TNF alpha signaling. Mechanistic studies indicate that in this context, XIAP is a positive modulator of TNF alpha induction whereas cellular inhibitor of apoptosis protein 1 negatively regulates TNF alpha-mediated apoptosis.

引用

页码：11493 / 11498

页数：6

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