Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression
Copyright policy )Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression
We describe a genome-wide gain-of-function screen for regulators of NF-kappaB, and identify Rap1 (Trf2IP), as an essential modulator of NF-kappaB-mediated pathways. NF-kappaB 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 (IkappaB kinases), and is crucial for the ability of IKKs to be recruited to, and phosphorylate, the p65 subunit of NF-kappaB to make it transcriptionally competent. Rap1-mutant mice display defective NF-kappaB activation and are resistant to endotoxic shock. Furthermore, levels of Rap1 are positively regulated by NF-kappaB, and human breast cancers with NF-kappaB hyperactivity show elevated levels of cytoplasmic Rap1. Similar to inhibiting NF-kappaB, 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.
- University of Florida United States
- Sanford Burnham Prebys Medical Discovery Institute United States
- University of Arizona United States
- Translational Genomics Research Institute United States
- St. Joseph's Hospital and Medical Center United States
Chromatin Immunoprecipitation, Blotting, Western, NF-kappa B, Apoptosis, Kaplan-Meier Estimate, Immunohistochemistry, Polymerase Chain Reaction, Shelterin Complex, Cell Line, I-kappa B Kinase, Mice, Cell Line, Tumor, Chromatography, Gel, Animals, Humans, Immunoprecipitation, Phosphorylation, RNA, Small Interfering, HeLa Cells, Protein Binding
Chromatin Immunoprecipitation, Blotting, Western, NF-kappa B, Apoptosis, Kaplan-Meier Estimate, Immunohistochemistry, Polymerase Chain Reaction, Shelterin Complex, Cell Line, I-kappa B Kinase, Mice, Cell Line, Tumor, Chromatography, Gel, Animals, Humans, Immunoprecipitation, Phosphorylation, RNA, Small Interfering, HeLa Cells, Protein Binding
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