@article{ff938063d58a4192aafac2b37458d2e8,
title = "Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression",
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.",
author = "Hsiangling Teo and Sourav Ghosh and Hendrik Luesch and Arkasubhra Ghosh and Wong, {Ee Tsin} and Najib Malik and Anthony Orth and {De Jesus}, Paul and Perry, {Anthony S.} and Oliver, {Jeffrey D.} and Tran, {Nhan L.} and Speiser, {Lisa J.} and Marc Wong and Enrique Saez and Peter Schultz and Chanda, {Sumit K.} and Verma, {Inder M.} and Vinay Tergaonkar",
note = "Funding Information: We wish to thank the Agency for Science Technology and Research, Singapore (A*Star) for funding and support to the V.T. laboratory. I.M.V. is an American Cancer Society Professor of Molecular Biology, and holds the Joan and Irwin Jacobs Chair in Exemplary Life Sciences. This work was supported in part by grants from the Leducq Foundation, Meriaux Foundation, Ellison Medical Foundation, Ipsen/ Biomeasure, Sanofi Aventis, and the H.N. and Frances C. Berger Foundation. We thank T. Murphy and N. Tonnu for help with the intial investigations involved in this work. We are grateful to B. Li and T. De Lange for Rap1 deletion constructs and P. Lieberman for the Rap1 shRNA vector. We thank J. Karlseder for helpful discussions.",
year = "2010",
month = aug,
doi = "10.1038/ncb2080",
language = "English (US)",
volume = "12",
pages = "758--767",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "8",
}