Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB

Chen, Lin Feng; Mu, Yajun; Greene, Warner C.

doi:10.1093/emboj/cdf660

Cited by 712 publications

(743 citation statements)

References 54 publications

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“…This is similar to what we have previously observed for Bcr [22]. However, an alternate mechanism for activating NF-κB involves phosphorylation of the transactivation domain [37][38][39]. Several studies have shown that the transcriptional activity of NF-κB is increased by phosphorylation at ser276, ser311, ser529 or ser536 [40][41][42][43].…”

Section: Discussionsupporting

confidence: 89%

ROCK I-mediated activation of NF-κB by RhoB

Rodrı́guez

Sahay

Olabisi

et al. 2007

Cellular Signalling

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RhoB is a short-lived protein whose expression is increased by a variety of extra-cellular stimuli including UV irradiation, epidermal growth factor (EGF) and transforming growth factor β (TGF-β). Whereas most Rho proteins are modified by the covalent attachment of a geranylgeranyl group, RhoB is unique in that it can exist in either a geranylgeranylated (RhoB-GG) or a farnesylated (RhoB-F) form. Although each form is proposed to have different cellular functions, the signaling events that underlie these differences are poorly understood. Here we show that RhoB can activate NF-κB signaling in multiple cell types. Whereas RhoB-F is a potent activator of NF-κB, much weaker activation is observed for RhoB-GG, RhoA, and RhoC. NF-κB activation by RhoB is not associated with increased nuclear translocation of RelA/p65, but rather, by modification of the RelA/p65 transactivation domain. Activation of NF-κB by RhoB is dependent upon ROCK I but not PRK I. Thus, ROCK I cooperates with RhoB to activate NF-κB, and suppression of ROCK I activity by genetic or pharmacological inhibitors blocks NF-κB activation. Suppression of RhoB activity by dominant-inhibitory mutants, or siRNA, blocks NF-κB activation by Bcr, and TSG101, but not by TNFα or oncogenic Ras. Collectively, these observations suggest the existence of an endosomeassociated pathway for NF-κB activation that is preferentially regulated by the farnesylated form of RhoB.

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Section: Discussionsupporting

confidence: 89%

ROCK I-mediated activation of NF-κB by RhoB

Rodrı́guez

Sahay

Olabisi

et al. 2007

Cellular Signalling

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“…Once in the nucleus, NF-kB induces transcription of cell-cycle, proliferation, migration and apoptosis genes (Piva et al, 2006). Phosphorylation of NF-kB on Ser276 recruits HAT-containing complexes to target promoters (Zhong et al, 2002), while acetylation of NF-kB on multiple lysines affects both its DNA binding and transactivation activity (Chen et al, 2002;Kiernan et al, 2003). Several class I HDACs as well as SIRT1 can deacetylate NF-kB (Ashburner et al, 2001;Chen et al, 2002;Zhong et al, 2002;Yeung et al, 2004).…”

Section: Activation Of Sirt1 May Prevent Age-related Cancersmentioning

confidence: 99%

“…Phosphorylation of NF-kB on Ser276 recruits HAT-containing complexes to target promoters (Zhong et al, 2002), while acetylation of NF-kB on multiple lysines affects both its DNA binding and transactivation activity (Chen et al, 2002;Kiernan et al, 2003). Several class I HDACs as well as SIRT1 can deacetylate NF-kB (Ashburner et al, 2001;Chen et al, 2002;Zhong et al, 2002;Yeung et al, 2004). A direct interaction between endogenous SIRT1 and NF-kB not only promotes the deacetylation of NF-kB on lysine 310, but also of HATs on target promoters and local histone proteins to actively repress target gene expression (Yeung et al, 2004).…”

Section: Activation Of Sirt1 May Prevent Age-related Cancersmentioning

confidence: 99%

Sirtuins: critical regulators at the crossroads between cancer and aging

2007

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Sirtuins (SIRTs 1À7), or class III histone deacetylases (HDACs), are protein deacetylases/ADP ribosyltransferases that target a wide range of cellular proteins in the nucleus, cytoplasm, and mitochondria for post-translational modification by acetylation (SIRT1, -2, -3 and -5) or ADP ribosylation (SIRT4 and -6). The orthologs of sirtuins in lower organisms play a critical role in regulating lifespan. As cancer is a disease of aging, we discuss the growing implications of the sirtuins in protecting against cancer development. Sirtuins regulate the cellular responses to stress and ensure that damaged DNA is not propagated and that mutations do not accumulate. SIRT1 also promotes replicative senescence under conditions of chronic stress. By participating in the stress response to genomic insults, sirtuins are thought to protect against cancer, but they are also emerging as direct participants in the growth of some cancers. Here, we review the growing implications of sirtuins both in cancer prevention and as specific and novel cancer therapeutic targets.

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“…Interestingly, in cultured cells, it was shown that CBP and p300 acetylate the NFκB p65 subunit in a stimulus-dependent manner, which, subsequently, could be deacetylated through HDAC3. p65 acetylation regulates NFκB nuclear function, and acetylation increases its DNA binding affinity (K221) and transcriptional activity (K301) [194]. In contrast, IκBα binds and sequesters the deacetylated form, switching NFκB function off [195].…”

Section: Non-histone Protein Acetylation In Synaptic Plasticity and Mmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB

Cited by 712 publications

References 54 publications

ROCK I-mediated activation of NF-κB by RhoB

ROCK I-mediated activation of NF-κB by RhoB

Sirtuins: critical regulators at the crossroads between cancer and aging

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

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