The role of RelA (p65) threonine 505 phosphorylation in the regulation of cell growth, survival, and migration

Msaki, Aichi; Sánchez, Ana M.; Koh, Li Fang; Barré, Benjamin; Rocha, Sónia; Perkins, Neil D.; Johnson, Renée

doi:10.1091/mbc.e11-04-0280

Cited by 40 publications

(50 citation statements)

References 43 publications

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“…However, whether phosphorylation at these sites might affect the gene expression program controlling cell motility remains elusive. Interestingly, in contrast to RelB serine 472 phosphorylation that promotes fibroblast migration, which we report here, RelA phosphorylation at threonine 505, which is inducible by the Chk1 kinase, has been implicated as a negative regulator of constitutive fibroblast migration (30). Importantly, contrary to RelB serine 472, RelA threonine 505 phosphorylation is not inducible upon TNFα treatment (31).…”

Section: Discussioncontrasting

confidence: 55%

IKK phosphorylates RelB to modulate its promoter specificity and promote fibroblast migration downstream of TNF receptors

Authier

Billot

Derudder

et al. 2014

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

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TNFα is a potent cytokine that plays a critical role in numerous cellular processes, particularly immune and inflammatory responses, programmed cell death, angiogenesis, and cell migration. Thus, understanding the molecular mechanisms that mediate TNFα-induced cellular responses is a crucial issue. It is generally accepted that global DNA binding activity of the NF-κB avian reticuloendotheliosis viral (v-rel) oncogene related B (RelB) subunit is not induced upon TNFα treatment in fibroblasts, despite its TNFα-induced nuclear accumulation. Here, we demonstrate that RelB plays a critical role in promoting fibroblast migration upon prolonged TNFα treatment. We identified the two kinases IκB kinase α (IKKα) and IκB kinase β (IKKβ) as RelB interacting partners whose activation by TNFα promotes RelB phosphorylation at serine 472. Once phosphorylated on serine 472, nuclear RelB dissociates from its interaction with the inhibitory protein IκBα and binds to the promoter of critical migrationassociated genes, such as the matrix metallopeptidase 3 (MMP3). Further, we show that RelB serine 472 phosphorylation status controls MMP3 expression and promigration activity downstream of TNF receptors. Our findings provide new insights into the regulation of RelB activity and reveal a novel link between selective NF-κB target gene expression and cellular response in response to TNFα.TNFalpha | NF-kappaB | metalloproteinase | posttranslational modification

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Section: Discussioncontrasting

confidence: 55%

IKK phosphorylates RelB to modulate its promoter specificity and promote fibroblast migration downstream of TNF receptors

Authier

Billot

Derudder

et al. 2014

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

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“…Membranes were blocked and stained in 1% skimmed milk powder (Campina) and 3% BSA (Roche) in PBS with 0.1% Tween 20 for assaying total NF-kBp65 (1:100 dilution of clone sc-8008; Santa Cruz Biotechnology), or 2% skimmed milk powder and 2% BSA in TBST for assaying S536-phosphorylated NFkBp65 (1:1000 dilution of clone 93H1; Cell Signaling Technology). Membranes were blocked for 1 h at room temperature, stained overnight with primary Abs (including mouse or rabbit [20][21][22][23][24][25][26][27][28][29][30][31][32][33] antiactin, 1:10,000 dilution; Sigma-Aldrich), and stained for 1 h at room temperature with corresponding secondary Abs (diluted 1:5000): goat anti-mouse IgG IRDye 800CW, goat anti-rabbit IgG IRDye 800CW, goat anti-mouse IRDye 680RD (all three from LI-COR Biosciences), or goat anti-rabbit IgG Alexa Fluor 640 (Invitrogen). Membranes were scanned by using an Odyssey Infrared Imaging System (LI-COR Biosciences).…”

Section: Phosphorylation Of Nf-kbp65mentioning

confidence: 99%

“…In addition to regulation of nuclear translocation, NF-kB activation also depends on posttranslational modifications (PTMs) such as phosphorylation, acetylation, ubiquitination, sumoylation, and nitrosylation (17). For instance, phosphorylation of S536 or S276 on p65 leads to activation of NF-kB-mediated transcription (18,19), whereas phosphorylation of S547 or T505 on p65 renders NF-kB inactive, preventing transcription of its target genes (20,21). Likewise, acetylation of K122 and K123 inhibits NF-kBp65 (22), whereas acetylation of K310 activates NF-kBp65-mediated transcription (23).…”

mentioning

confidence: 99%

DC-SCRIPT Regulates IL-10 Production in Human Dendritic Cells by Modulating NF-κBp65 Activation

Søndergaard

Poghosyan

Hontelez

et al. 2015

The Journal of Immunology

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The balance between tolerance and immunity is important for the outcome of an infection or cancer, and dendritic cells (DCs) are key regulators of this balance. DC-specific transcript (DC-SCRIPT) is a protein expressed by DCs and has been demonstrated to suppress both TLR-mediated expression of IL-10 and glucocorticoid receptor–mediated transcription of glucocorticoid-induced leucine zipper (GILZ). Because GILZ is known to promote IL-10 production, we investigated whether these two processes are linked. Dual-knockdown and inhibition experiments demonstrated that neither GILZ nor glucocorticoid receptor play a role in TLR-induced IL-10 production after DC-SCRIPT knockdown. The NF-κB pathway is another route involved in IL-10 production after DC activation. Strikingly, inhibition of NF-κB led to a decreased TLR-mediated IL-10 production in DC-SCRIPT knockdown DCs. Moreover, DC-SCRIPT knockdown DCs showed enhanced phosphorylation, acetylation, and IL10 enhancer binding of the NF-κB subunit p65. These data demonstrate that besides nuclear receptor regulation, DC-SCRIPT also modulates activation of NF-κBp65 after TLR activation in human DCs.

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“…The nuclear factor-B (NFB) transcriptional factor, a key controller in regulating the immune response, has been implicated in modulating the cell proliferation, differentiation, and motility (9,10). In a resting state, NFB remains in the cytoplasm by tightly binding to the inhibitory nuclear factor of light polypeptide gene enhancer in B-cells inhibitor (IB)␣ protein (11).…”

mentioning

confidence: 99%

Progesterone Receptor-NFκB Complex Formation Is Required for Progesterone-Induced NFκB Nuclear Translocation and Binding Onto the p53 Promoter

et al. 2015

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We previously demonstrated that progesterone (P4) up-regulates p53 expression in human umbilical venous endothelial cells (HUVECs) through P4 receptor (PR) activation of extranuclear signaling pathways. However, the involvement of nuclear PR in P4-increased p53 expression is still unclear. Here, the molecular mechanism underlying PR-regulated p53 expression in HUVECs was investigated. Treatment with P4 increased nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α phosphorylation (IκBα and nuclear factor-κB (NFκB) nuclear translocation. Interestingly, P4 also increased PR-A, but not PR-B, nuclear translocation in HUVECs. Immunoprecipitation assay illustrated that P4 increased the formation of PR-A-NFκB complex in both the cytosol and the nucleus of HUVEC. Chromatin immunoprecipitation assay showed an interaction between PR and the NFκB binding motif on the p53 promoter. Ablation of the NFκB binding motif in the p53 promoter completely abolished P4-increased p53 promoter activity. In the absence of P4, overexpression of NFκB did not increase NFκB nuclear translocation. In contrast, treatment of NFκB-overexpressing HUVECs with P4 for only 4 hours, which is much shorter than the time (21.5 h) required for P4-induced IκBα phosphorylation, increased NFκB nuclear translocation. Blockade of PR activity abolished this effect. Taken together, these results uncover a novel role of PR for P4-induced NFκB nuclear translocation and suggest that PR-A-NFκB complex formation is required for NFκB nuclear translocation and binding onto the p53 promoter in HUVECs. Our data indicate that both nuclear and extranuclear signaling pathways of PR are involved in P4-regulated p53 expression in HUVECs.

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The role of RelA (p65) threonine 505 phosphorylation in the regulation of cell growth, survival, and migration

Cited by 40 publications

References 43 publications

IKK phosphorylates RelB to modulate its promoter specificity and promote fibroblast migration downstream of TNF receptors

IKK phosphorylates RelB to modulate its promoter specificity and promote fibroblast migration downstream of TNF receptors

DC-SCRIPT Regulates IL-10 Production in Human Dendritic Cells by Modulating NF-κBp65 Activation

Progesterone Receptor-NFκB Complex Formation Is Required for Progesterone-Induced NFκB Nuclear Translocation and Binding Onto the p53 Promoter

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