Functional relevance of novel p300-mediated lysine 314 and 315 acetylation of RelA/p65

Buerki, Christine; Rothgiesser, Karin; Valovka, Taras; Owen, Heather; Rehrauer, Hubert; Fey, Monika; Lane, William S.; Hottiger, Michael O.

doi:10.1093/nar/gkn003

Cited by 89 publications

(108 citation statements)

References 52 publications

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“…We did not detect recruitment of p65 acetylated at Lys-122/123, Lys-218, Lys-221, and Lys-310 to the IL-8, TNF, or IL-6 promoters (data not shown). Interestingly, acetylation of p65 at Lys-314/ 315 has been associated previously with a differential regulation of NFB target genes (43)(44)(45). In contrast to p65, however, Lys-314/315 ac-p65 occupancy at the IL-8 promoter was not dependent on IKK activity (Fig.…”

Section: Vorinostat-induced Il-8/cxcl8 Expression Is Dependent On Ikksupporting

confidence: 53%

Histone Deacetylase (HDAC) Inhibition Induces IκB Kinase (IKK)-dependent Interleukin-8/CXCL8 Expression in Ovarian Cancer Cells

Gatla

Zou

Uddin

et al. 2017

Journal of Biological Chemistry

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Section: Vorinostat-induced Il-8/cxcl8 Expression Is Dependent On Ikksupporting

confidence: 53%

Histone Deacetylase (HDAC) Inhibition Induces IκB Kinase (IKK)-dependent Interleukin-8/CXCL8 Expression in Ovarian Cancer Cells

Gatla

Zou

Uddin

et al. 2017

Journal of Biological Chemistry

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“…Posttranslational modifications of NF-κB, reviewed recently (7,15), include the acetylation of p65, which is inducibly modified at several sites, including K122, K123, K218, K221, K310, K314, and K315 under different conditions, with different effects on activity (16)(17)(18). In 293C6 cells, we observed the methylation of both K218 and K221 in response to activation of NF-κB.…”

Section: Discussionmentioning

confidence: 70%

“…For p53, K372 is methylated by the H3K4 methylase SET7/9, enhancing the subsequent acetylation of the same residue and in turn stabilizing p53 (24). In addition, the previously identified acetylated sites K314/K315 that are modified by CBP/p300 (18) were also recently identified as substrates for monomethylation catalyzed by the histone H3K4 methylase SET9 (25). The ways in which lysine methylation and acetylation are controlled to finely regulate NF-κB activity in normal and tumor cells, and the mechanisms that control the timing, location, intensity, residue specificity, and type of modification, are important issues for future research.…”

Section: Discussionmentioning

confidence: 95%

Regulation of NF-κB by NSD1/FBXL11-dependent reversible lysine methylation of p65

Lü

Jackson²,

Wang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

258

213

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NF-κB, a central coordinator of immune and inflammatory responses, must be tightly regulated. We describe a NF-κB regulatory pathway that is driven by reversible lysine methylation of the p65 subunit, carried out by a lysine methylase, the nuclear receptorbinding SET domain-containing protein 1 (NSD1), and a lysine demethylase, F-box and leucine-rich repeat protein 11 (FBXL11). Overexpression of FBXL11 inhibits NF-κB activity, and a high level of NSD1 activates NF-κB and reverses the inhibitory effect of FBXL11, whereas reduced expression of NSD1 decreases NF-κB activation. The targets are K218 and K221 of p65, which are methylated in cells with activated NF-κB. Overexpression of FBXL11 slowed the growth of HT29 cancer cells, whereas shRNA-mediated knockdown had the opposite effect, and these phenotypes were dependent on K218/K221 methylation. In mouse embryo fibroblasts, the activation of most p65-dependent genes relied on K218/K221 methylation. Importantly, expression of the FBXL11 gene is driven by NF-κB, revealing a negative regulatory feedback loop. We conclude that reversible lysine methylation of NF-κB is an important element in the complex regulation of this key transcription factor. [RelA (p65), RelB, c-Rel, NF-κB1 (p50), and NF-κB2 (p52)], the p65/p50 heterodimer functions most often in the "classical" signaling pathway (1). Constitutive NF-κB activation is frequently associated with a number of pathological conditions, including inflammation and cancer, and is well known to be involved in tumor angiogenesis and invasiveness (2). Loss of the normal regulation of NF-κB is a major contributor to the deregulated growth, resistance to apoptosis, and propensity to metastasize observed in many different cancers (3). Our data, showing NF-κB activation in many cancer-derived cell lines (4, 5), further support the strong correlation between constitutive NF-κB activation and cancer. Thus, understanding the complexity of NF-κB-dependent signaling is an important aspect of dealing with these diseases.NF-κB has a variety of functions and is regulated by hundreds of different stimuli in different cell types (6). Specialized control of NF-κB activity is critical for achieving its normal transient activation in response to stress. Regardless of the stimulus, all pathways leading to NF-κB activation depend on inducing posttranslational modifications of the IκB kinase, IκB proteins, or NF-κB subunits. These regulatory modifications, including phosphorylation, ubiquitination, acetylation, sumolation, and nitrosylation, vary depending on the specific stimulus and context (7).We have developed a lentiviral validation-based insertional (VBIM) method to create mutant cell lines in which the overexpression of specific cellular proteins, driven by inserted CMV promoters, is responsible for altered phenotypes. We used this method to identify the F-box and leucine-rich repeat protein 11 (FBXL11) as a potent negative regulator of NF-κB and to show that its demethylase activity was required for this function (8). FBXL11, previous...

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“…Although acetylation of the K218, K221, and K310 residues of p65 increases the transcriptional activity of NF-B, acetylation of the K122 and K123 residues reduces the transcriptional activity of NF-B by facilitating the nuclear export of p65 (25,26). In addition, acetylation at residues K314 and K315 of p65 has been shown to be important for NF-Bdependent transcription (36). In this study, we found that the acetylation of residues K314 and K315 of p65 was, at least in osteoclasts, of less importance for NF-B-dependent transcription.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway

Iezaki

Fukasawa

Park

et al. 2016

Molecular and Cellular Biology

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Bone homeostasis is maintained by the synergistic actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Here, we show that the transcriptional coactivator/repressor interferon-related developmental regulator 1 (Ifrd1) is expressed in osteoclast lineages and represents a component of the machinery that regulates bone homeostasis. Ifrd1 expression was transcriptionally regulated in preosteoclasts by receptor activator of nuclear factor B (NF-B) ligand (RANKL) through activator protein 1. Global deletion of murine Ifrd1 increased bone formation and decreased bone resorption, leading to a higher bone mass. Deletion of Ifrd1 in osteoclast precursors prevented RANKL-induced bone loss, although no bone loss was observed under normal physiological conditions. RANKL-dependent osteoclastogenesis was impaired in vitro in Ifrd1-deleted bone marrow macrophages (BMMs). Ifrd1 deficiency increased the acetylation of p65 at residues K122 and K123 via the inhibition of histone deacetylase-dependent deacetylation in BMMs. This repressed the NF-B-dependent transcription of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), an essential regulator of osteoclastogenesis. These findings suggest that an Ifrd1/NF-B/NFATc1 axis plays a pivotal role in bone remodeling in vivo and represents a therapeutic target for bone diseases.

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Functional relevance of novel p300-mediated lysine 314 and 315 acetylation of RelA/p65

Cited by 89 publications

References 52 publications

Histone Deacetylase (HDAC) Inhibition Induces IκB Kinase (IKK)-dependent Interleukin-8/CXCL8 Expression in Ovarian Cancer Cells

Histone Deacetylase (HDAC) Inhibition Induces IκB Kinase (IKK)-dependent Interleukin-8/CXCL8 Expression in Ovarian Cancer Cells

Regulation of NF-κB by NSD1/FBXL11-dependent reversible lysine methylation of p65

Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway

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