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- Title
Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression.
- Authors
Hsiangling Teo; Ghosh, Sourav; Luesch, Hendrik; Ghosh, Arkasubhra; Ee Tsin Wong; Malik, Najib; Orth, Anthony; de Jesus, Paul; Perry, Anthony S.; Oliver, Jeffrey D.; Tran, Nhan L.; Speiser, Lisa J.; Wong, Marc; Saez, Enrique; Schultz, Peter; Chanda, Sumit K.; Verma, Inder M.; Tergaonkar, Vinay
- Abstract
We describe a genome-wide gain-of-function screen for regulators of NF-κB, and identify Rap1 (Trf2IP), as an essential modulator of NF-κB-mediated pathways. NF-κB is induced by ectopic expression of Rap1, whereas its activity is inhibited by Rap1 depletion. In addition to localizing on telomeres, mammalian Rap1 forms a complex with IKKs (IκB kinases), and is crucial for the ability of IKKs to be recruited to, and phosphorylate, the p65 subunit of NF-κB to make it transcriptionally competent. Rap1-mutant mice display defective NF-κB activation and are resistant to endotoxic shock. Furthermore, levels of Rap1 are positively regulated by NF-κB, and human breast cancers with NF-κB hyperactivity show elevated levels of cytoplasmic Rap1. Similar to inhibiting NF-κB, knockdown of Rap1 sensitizes breast cancer cells to apoptosis. These results identify the first cytoplasmic role of Rap1 and provide a mechanism through which it regulates an important signalling cascade in mammals, independent of its ability to regulate telomere function.
- Publication
Nature Cell Biology, 2010, Vol 12, Issue 8, p758
- ISSN
1465-7392
- Publication type
Academic Journal
- DOI
10.1038/ncb2080