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  current news   Press   selected story    
     
  28th July 2010  
  Telomere independent Rap1 is an IKK-adaptor and regulates NFκB- dependent gene expression
 
 




Authors
Hsiangling Teo1, Sourav Ghosh2,9 , Hendrik Luesch3,4,9 , Arkasubhra Ghosh1,9, Ee Tsin Wong1,9,  Najib Malik1, Anthony Orth4, Paul de Jesus4, Anthony S Perry5, Jeffrey D. Oliver5, Nhan L. Tran6, Lisa J. Speiser2, Marc Wong1, Enrique Saez4,  Peter Schultz4, Sumit K Chanda4,7, Inder M Verma8 and Vinay Tergaonkar1

1 - Laboratory of NFkB Signaling, IMCB, Proteos, Singapore, 138673.
2 - Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, AZ, 85440.
3 - Department of Medicinal Chemistry, University of Florida, Gainesville, FL, 32610.
4 - Genomics Institute of the Novartis Research Foundation, San Diego, CA, 92121.
5 - Department of Pathology, St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85004.
6 - CNS Tumor Research Laboratory, Translational Genomics Research Institute, Phoenix, AZ, 85004.
7 - Infectious & Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
8 - Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA, 92037.
9 - Equal contribution.

Published online in Nature Cell Biology, 11 July 2010 | doi:10.1038/ncb2080.

Abstract
We describe a genome-wide gain-of-function-screen for regulators of NFκB and identify Rap1 (Trf2IP), as an essential modulator of this pathway. Ectopic expression of Rap1 augments, while its depletion impedes NFκB activity. In addition to localizing on telomeres, mammalian Rap1 exists in a complex with IKKs and is crucial for the ability of IKKs to be recruited to and to phosphorylate the p65 subunit of NFκB and hence make it transcriptionally competent. Rap1 mutant mice display defective NFκB activation and are resistant to endotoxic shock. Rap1 levels in turn are positively regulated by NFκB and human breast cancers with NFκB hyperactivity show elevated levels of cytoplasmic Rap1. Much like inhibiting NFκB, knocking-down Rap1, sensitizes breast cancer cells to apoptosis. These results identify the first cytoplasmic role of Rap1 and provide a mechanism by which it regulates an important signaling cascade in mammals, independent of its ability to regulate telomere function.

Figure Legend:
Rap1 mutant mice are resistant to endotoxic shock and show defective NFκB signaling in response to LPS. A) Genotyping of Rap1 mice using the primers shown in (A) and described in materials and methods. +/+ is WT and m/+ is heterozygous for the gene trap allele. B) β-galactosidase staining in WT and Rap1m/+ embryos at E12.5. C) Western blot analysis of Rap1 protein from 2 independent WT (+/+) and Heterozygous (m/+) mice. D) Kaplan-Meier survival plot of wild-type (+/+) and Rap1 heterozygous (m/+) mutant mice (littermates, n=5) after administration of LPS (30mg LPS/kg). Mice were monitored for 4 days after injection. E) WT (+/+) and Rap1 heterozygous (m/+) mutant mice (littermates) were challenged with increasing dosage of LPS (0.5mg, 1mg and 2mg) as indicated at the bottom of the panel. A pair of control mice was injected with equal volume of PBS and used as controls (0). Gene expression in splenocytes for the indicated genes (on the top of the panel) was quantified by real-time PCR. Results are representative of 3 independent experiments. F) A model based on our studies. Mammalian Rap1 is associated with the members of the IKK complex. In response to NFκB activating stimuli, IκB proteins are degraded by IKK mediated phosphorylation, a reaction that is not modulated by Rap1. Rap1:IKK interaction however is essential for phosphorylation of p65 subunit at serine-536 as indicated by the red arrow. Modified p65 is efficient in transcribing its target genes. Activation of NFκB is paralleled by increase in Rap1 levels (indicated by dotted lines).

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