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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 758-767 |
| Number of pages | 10 |
| Journal | Nature |
| Volume | 12 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2010 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cell Biology
Cite this
Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression. / Teo, Hsiangling; Ghosh, Sourav; Luesch, Hendrik; Ghosh, Arkasubhra; Wong, Ee Tsin; Malik, Najib; Orth, Anthony; De Jesus, Paul; Perry, Anthony S.; Oliver, Jeffrey D.; Tran, Nhan; Speiser, Lisa J.; Wong, Marc; Saez, Enrique; Schultz, Peter; Chanda, Sumit K.; Verma, Inder M.; Tergaonkar, Vinay.
In: Nature, Vol. 12, No. 8, 08.2010, p. 758-767.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression
AU - Teo, Hsiangling
AU - Ghosh, Sourav
AU - Luesch, Hendrik
AU - Ghosh, Arkasubhra
AU - Wong, Ee Tsin
AU - Malik, Najib
AU - Orth, Anthony
AU - De Jesus, Paul
AU - Perry, Anthony S.
AU - Oliver, Jeffrey D.
AU - Tran, Nhan
AU - Speiser, Lisa J.
AU - Wong, Marc
AU - Saez, Enrique
AU - Schultz, Peter
AU - Chanda, Sumit K.
AU - Verma, Inder M.
AU - Tergaonkar, Vinay
PY - 2010/8
Y1 - 2010/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77955171057&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77955171057&partnerID=8YFLogxK
U2 - 10.1038/ncb2080
DO - 10.1038/ncb2080
M3 - Article
C2 - 20622870
AN - SCOPUS:77955171057
VL - 12
SP - 758
EP - 767
JO - Nature
JF - Nature
SN - 0028-0836
IS - 8
ER -