Author: ["Hsiangling Teo","Sourav Ghosh","Hendrik Luesch","Arkasubhra Ghosh","Ee Tsin Wong","Najib Malik","Anthony Orth","Paul de Jesus","Anthony S. Perry","Jeffrey D. Oliver","Nhan L. Tran","Lisa J. Speiser","Marc Wong","Enrique Saez","Peter Schultz","Sumit K. Chanda","Inder M. Verma","Vinay Tergaonkar"]
CITE.CC academic search helps you expand the influence of your papers.
Abstract
Mammalian Rap1 protein is found to have a non-telomeric function in regulating the substrate specificity of IKKs towards the p65 subunit of NF-κB, leading to NF-κB transcriptional activity. 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.Cite this article
Teo, H., Ghosh, S., Luesch, H. et al. Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression. Nat Cell Biol 12, 758–767 (2010). https://doi.org/10.1038/ncb2080 