Oxidative stress-dependent regulation of Forkhead box O4 activity by nemo-like kinase.
Forkhead box O (FOXO) transcription factors are involved in various cellular processes, including cell proliferation, stress resistance, metabolism, and longevity. Regulation of FOXO transcriptional activity occurs mainly through a variety of post-translational modifications, including phosphorylation, acetylation, and ubiquitination. Here we describe nemo-like kinase (NLK) as a novel regulator of FOXOs. ... NLK binds to and phosphorylates FOXO1, FOXO3a, and FOXO4 on multiple residues. NLK acts as a negative regulator of FOXO transcriptional activity. For FOXO4 we show that NLK-mediated loss of FOXO4 activity co-occurs with inhibition of FOXO4 monoubiquitination. Previously, we have shown that oxidative stress-induced monoubiquitination of FOXO4 stimulates its transactivation, which leads to activation of an antioxidant defensive program. Conversely, NLK-dependent inhibition of FOXO4 activity can provide a means to downregulate this defensive program, when oxidative stress reaches a level beyond which repair is no longer feasible and cells need to undergo apoptosis.
Mesh Terms:
Animals, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Mice, Oxidative Stress, Protein-Serine-Threonine Kinases, Transcription Factors, Ubiquitination
Animals, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Mice, Oxidative Stress, Protein-Serine-Threonine Kinases, Transcription Factors, Ubiquitination
Antioxid. Redox Signal.
Date: Feb. 15, 2011
PubMed ID: 20874444
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