Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression

Laboratory of NFkappaB Signaling, Proteos, Singapore 138673, Singapore.
Nature Cell Biology (Impact Factor: 20.06). 08/2010; 12(8):758-67. DOI: 10.1038/ncb2080
Source: PubMed

ABSTRACT 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.

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    • "By generating a whole-body Rap1-deficient mouse model, we show here that the mammalian telomere-binding protein RAP1 is dispensable for mouse development and adult viability, in contrast to that previously reported by Teo et al. (2010) and in agreement with Sfeir et al. (2010). In agreement with our previous findings that RAP1 binds throughout chromosome arms (Martinez et al., 2010), we find a role for RAP1 in the transcriptional regulation of pathways involved in postnatal cellular energy metabolism. "
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