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


ABSTRACT: TNF? 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 TNF?-induced cellular responses is a crucial issue. It is generally accepted that global DNA binding activity of the NF-?B avian reticuloendotheliosis viral (v-rel) oncogene related B (RelB) subunit is not induced upon TNF? treatment in fibroblasts, despite its TNF?-induced nuclear accumulation. Here, we demonstrate that RelB plays a critical role in promoting fibroblast migration upon prolonged TNF? treatment. We identified the two kinases I?B kinase ? (IKK?) and I?B kinase ? (IKK?) as RelB interacting partners whose activation by TNF? promotes RelB phosphorylation at serine 472. Once phosphorylated on serine 472, nuclear RelB dissociates from its interaction with the inhibitory protein I?B? and binds to the promoter of critical migration-associated 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-?B target gene expression and cellular response in response to TNF?.

SUBMITTER: Authier H 

PROVIDER: S-EPMC4205659 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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

Authier Hélène H   Billot Katy K   Derudder Emmanuel E   Bordereaux Didier D   Rivière Pierre P   Rodrigues-Ferreira Sylvie S   Nahmias Clara C   Baud Véronique V  

Proceedings of the National Academy of Sciences of the United States of America 20140929 41


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, de  ...[more]

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