Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.redox.2020.101834
Title: Sustained IKK beta phosphorylation and NF-kappa B activation by superoxide-induced peroxynitrite-mediated nitrotyrosine modification of B56 gamma 3 and PP2A inactivation
Authors: Yee, Yi Hui
Chong, Stephen Jun Fei 
Kong, Li Ren 
Goh, Boon Cher 
Pervaiz, Shazib 
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
PROTEIN PHOSPHATASE 2A
HYDROGEN-PEROXIDE
REDOX REGULATION
KINASE IKK
CANCER
BCL-2
INFLAMMATION
APOPTOSIS
SUBUNIT
TRANSCRIPTION
Issue Date: 7-Apr-2021
Publisher: ELSEVIER
Citation: Yee, Yi Hui, Chong, Stephen Jun Fei, Kong, Li Ren, Goh, Boon Cher, Pervaiz, Shazib (2021-04-07). Sustained IKK beta phosphorylation and NF-kappa B activation by superoxide-induced peroxynitrite-mediated nitrotyrosine modification of B56 gamma 3 and PP2A inactivation. REDOX BIOLOGY 41. ScholarBank@NUS Repository. https://doi.org/10.1016/j.redox.2020.101834
Abstract: Apart from its physiological role in inflammation and immunity, the nuclear factor-kappa B (NF-κB) protein complex has been implicated in tumorigenesis and its progression. Here, we provide evidence that a pro-oxidant milieu is an upstream effector of oncogenic NF-κB signaling. Through pharmacological or genetic inhibition of SOD1, we show that elevated intracellular superoxide (O2[rad]-) mediates sustained IKK phosphorylation, and induces downstream degradation of IκBα, leading to the nuclear localization and transcriptional activation of NF-κB. Mechanistically, we show that such sustained NF-κB signaling is a function of protein phosphatase 2A (PP2A) inactivation brought about by the nitrative modification of its substrate-binding sub-unit B56γ. Importantly, the pro-oxidant driven NF-κB activation enhances the migratory and invasive potential of cancer cells. In summary, our work highlights the critical involvement of O2[rad]--dependent peroxynitrite production in inhibiting PP2A-mediated dephosphorylation of IKK, thereby facilitating cancers to acquire an invasive phenotype. Given that NF-κB is a key player of chronic inflammation and carcinogenesis, our work unravels a novel synergistic node involving O2[rad]--driven redox milieu and deregulated PP2A as a potential therapeutic target.
Source Title: REDOX BIOLOGY
URI: https://scholarbank.nus.edu.sg/handle/10635/224536
ISSN: 2213-2317
DOI: 10.1016/j.redox.2020.101834
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