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

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.

journal_name

Nat Cell Biol

journal_title

Nature cell biology

authors

Teo H,Ghosh S,Luesch H,Ghosh A,Wong ET,Malik N,Orth A,de Jesus P,Perry AS,Oliver JD,Tran NL,Speiser LJ,Wong M,Saez E,Schultz P,Chanda SK,Verma IM,Tergaonkar V

doi

10.1038/ncb2080

subject

Has Abstract

pub_date

2010-08-01 00:00:00

pages

758-67

issue

8

eissn

1465-7392

issn

1476-4679

pii

ncb2080

journal_volume

12

pub_type

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