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Your search keyword '"Ee Tsin Wong"' showing total 4 results
Start Over Author "Ee Tsin Wong" Journal nature cell biology
4 results on '"Ee Tsin Wong"'

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

Author

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

Subjects
endocrine system, Gene knockdown, Kinase, Cell Biology, IκB kinase, Biology, Telomere, Cell biology, enzymes and coenzymes (carbohydrates), Cancer research, Phosphorylation, Ectopic expression, Rap1, Chromatin immunoprecipitation
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.

Published
2010

2. WIP1 phosphatase is a negative regulator of NF-kappaB signalling

Author

Sathyavageeswaran Shreeram, Mahathir Humaidi, Manprit Kaur Dhillion, Dmitry V. Bulavin, Vinay Tergaonkar, Cheok Chit Fang, Subhra K. Biswas, Joanne Chew, Amit Hazra, Hsiangling Teo, Ee Tsin Wong, and Eduardo López-Collazo

Subjects
Lipopolysaccharides, Protein subunit, Phosphatase, Gene Expression, Mice, Inbred Strains, Pyruvate dehydrogenase phosphatase, Biology, Models, Biological, p38 Mitogen-Activated Protein Kinases, Transactivation, Mice, Cell Line, Tumor, Sepsis, Phosphoprotein Phosphatases, Animals, Humans, p300-CBP Transcription Factors, Phosphorylation, RNA, Small Interfering, Mice, Knockout, Gene knockdown, Kinase, Tumor Necrosis Factor-alpha, NF-kappa B, Transcription Factor RelA, Animal Structures, Cell Biology, Fibroblasts, Molecular biology, Mice, Mutant Strains, Cell biology, Protein Phosphatase 2C, Cell culture, Spleen, HeLa Cells, Interleukin-1, Signal Transduction
Abstract

Post-translational modifications of NF-kappaB through phosphorylations enhance its transactivation potential. Much is known about the kinases that phosphorylate NF-kappaB, but little is known about the phosphatases that dephosphorylate it. By using a genome-scale siRNA screen, we identified the WIP1 phosphatase as a negative regulator of NF-kappaB signalling. WIP1-mediated regulation of NF-kappaB occurs in both a p38-dependent and independent manner. Overexpression of WIP1 resulted in decreased NF-kappaB activation in a dose-dependent manner, whereas WIP1 knockdown resulted in increased NF-kappaB function. We show that WIP1 is a direct phosphatase of Ser 536 of the p65 subunit of NF-kappaB. Phosphorylation of Ser 536 is known to be essential for the transactivation function of p65, as it is required for recruitment of the transcriptional co-activator p300. WIP1-mediated regulation of p65 regulated binding of NF-kappaB to p300 and hence chromatin remodelling. Consistent with our results, mice lacking WIP1 showed enhanced inflammation. These results provide the first genetic proof that a phosphatase directly regulates NF-kappaB signalling in vivo.

Published
2008

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

Author

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

Subjects
MAMMALIAN artificial chromosomes, IMMUNOMODULATORS, TELOMERES, SEPTIC shock, BREAST cancer
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. [ABSTRACT FROM AUTHOR]

Published
2010
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4. WIP1 phosphatase is a negative regulator of NF-κB signalling.

Author

Chew, Joanne, Biswas, Subhra, Shreeram, Sathyavageeswaran, Humaidi, Mahathir, Ee Tsin Wong, Dhillion, Manprit Kaur, Hsiangling Teo, Hazra, Amit, Cheok Chit Fang, López-Collazo, Eduardo, Bulavin, Dmitry V., and Tergaonkar, Vinay

Subjects
PHOSPHATASES, PHOSPHORYLATION, PROTEIN kinases, CHROMATIN, NF-kappa B, CYTOLOGY, BIOLOGICAL research
Abstract

Post-translational modifications of NF-κB through phosphorylations enhance its transactivation potential. Much is known about the kinases that phosphorylate NF-κB, but little is known about the phosphatases that dephosphorylate it. By using a genome-scale siRNA screen, we identified the WIP1 phosphatase as a negative regulator of NF-κB signalling. WIP1-mediated regulation of NF-κB occurs in both a p38-dependent and independent manner. Overexpression of WIP1 resulted in decreased NF-κB activation in a dose-dependent manner, whereas WIP1 knockdown resulted in increased NF-κB function. We show that WIP1 is a direct phosphatase of Ser 536 of the p65 subunit of NF-κB. Phosphorylation of Ser 536 is known to be essential for the transactivation function of p65, as it is required for recruitment of the transcriptional co-activator p300. WIP1-mediated regulation of p65 regulated binding of NF-κB to p300 and hence chromatin remodelling. Consistent with our results, mice lacking WIP1 showed enhanced inflammation. These results provide the first genetic proof that a phosphatase directly regulates NF-κB signalling in vivo. [ABSTRACT FROM AUTHOR]

Published
2009
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