title: NF-kappaB activation by combinations of NEMO SUMOylation and ATM activation stresses in the absence of DNA damage.
abstract: The inactive transcription factor NF-kappaB is localized in the cytoplasm and rapidly responds to a variety of extracellular factors and intracellular stress conditions to initiate multiple cellular responses. While the knowledge regarding NF-kappaB signaling pathways initiated by extracellular ligands is rapidly expanding, the mechanisms of activation by intracellular stress conditions are not well understood. We recently described a critical role for a small ubiquitin-like modifier (SUMO) modification of NF-kappaB essential modulator (NEMO), the regulatory subunit of the IkappaB kinase, in response to certain genotoxic stress conditions. One important unanswered question is whether the role of this modification is limited to the genotoxic agents or some other signaling pathways also employ SUMOylation of NEMO to regulate NF-kappaB activation. Here, we report that a variety of other stress conditions, including oxidative stress, ethanol exposure, heat shock and electric shock, also induce NEMO SUMOylation, thus demonstrating that DNA damage per se is not necessary for this NEMO modification to occur. Moreover, combinations of certain SUMO stress and ATM (ataxia telangiectasia mutated) activation conditions lead to NF-kappaB activation without inducing DNA damage. Our study helps to conceptualize how individual or a combination of different stress conditions may funnel into this previously unappreciated signal transduction mechanism to regulate the activity of the ubiquitous NF-kappaB transcription factor.
authors.affiliation: Cancer Biology Program, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Wuerzberger-Davis
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.forename: B J
authors.initials: BJ
authors.lastname: Seufzer
authors.forename: S
authors.initials: S
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003593:Cytoplasm; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004558:Electric Stimulation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D000431:Ethanol / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D018869:Heat-Shock Response / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D025842:SUMO-1 Protein; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D000431:Ethanol; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases