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

Hsiangling Teo, Sourav Ghosh, Hendrik Luesch, Arkasubhra Ghosh, Ee Tsin Wong, Najib Malik, Anthony Orth, Paul De Jesus, Anthony S. Perry, Jeffrey D. Oliver, Nhan Tran, Lisa J. Speiser, Marc Wong, Enrique Saez, Peter Schultz, Sumit K. Chanda, Inder M. Verma, Vinay Tergaonkar

Research output: Contribution to journalArticle

104 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)758-767
Number of pages10
JournalNature
Volume12
Issue number8
DOIs
StatePublished - Aug 2010
Externally publishedYes

Fingerprint

Telomere
Breast Neoplasms
Gene Expression
Septic Shock
Mammals
Phosphotransferases
Genome
Apoptosis
Ectopic Gene Expression

ASJC Scopus subject areas

  • Cell Biology

Cite this

Teo, H., Ghosh, S., Luesch, H., Ghosh, A., Wong, E. T., Malik, N., ... Tergaonkar, V. (2010). Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression. Nature, 12(8), 758-767. https://doi.org/10.1038/ncb2080

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 journalArticle

Teo, H, Ghosh, S, Luesch, H, Ghosh, A, Wong, ET, Malik, N, Orth, A, De Jesus, P, Perry, AS, Oliver, JD, Tran, N, Speiser, LJ, Wong, M, Saez, E, Schultz, P, Chanda, SK, Verma, IM & Tergaonkar, V 2010, 'Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression', Nature, vol. 12, no. 8, pp. 758-767. https://doi.org/10.1038/ncb2080
Teo H, Ghosh S, Luesch H, Ghosh A, Wong ET, Malik N et al. Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression. Nature. 2010 Aug;12(8):758-767. https://doi.org/10.1038/ncb2080
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. / Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression. In: Nature. 2010 ; Vol. 12, No. 8. pp. 758-767.
@article{ff938063d58a4192aafac2b37458d2e8,
title = "Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression",
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.",
author = "Hsiangling Teo and Sourav Ghosh and Hendrik Luesch and Arkasubhra Ghosh and Wong, {Ee Tsin} and Najib Malik and Anthony Orth and {De Jesus}, Paul and Perry, {Anthony S.} and Oliver, {Jeffrey D.} and Nhan Tran and Speiser, {Lisa J.} and Marc Wong and Enrique Saez and Peter Schultz and Chanda, {Sumit K.} and Verma, {Inder M.} and Vinay Tergaonkar",
year = "2010",
month = "8",
doi = "10.1038/ncb2080",
language = "English (US)",
volume = "12",
pages = "758--767",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "8",

}

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 -