Premium
Transcriptional activation of the NF‐κB p65 subunit by mitogen‐ and stress‐activated protein kinase‐1 (MSK1)
Author(s) -
Vermeulen Linda,
De Wilde Gert,
Van Damme Petra,
Vanden Berghe Wim,
Haegeman Guy
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg139
Subject(s) - protein subunit , biology , library science , microbiology and biotechnology , computer science , genetics , gene
Nuclear factor κB (NF‐κB) is one of the key regulators of transcription of a variety of genes involved in immune and inflammatory responses. NF‐κB activity has long been thought to be regulated mainly by IκB family members, which keep the transcription factor complex in an inactive form in the cytoplasm by masking the nuclear localization signal. Nowadays, the importance of additional mechanisms controlling the nuclear transcription potential of NF‐κB is generally accepted. We show that the mitogen‐activated protein kinase inhibitors SB203580 and PD98059 or U0126, as well as a potent mitogen‐ and stress‐ activated protein kinase‐1 (MSK1) inhibitor H89, counteract tumor necrosis factor (TNF)‐mediated stimulation of p65 transactivation capacity. Muta tional analysis of p65 revealed Ser276 as a target for phosphorylation and transactivation in response to TNF. Moreover, we identified MSK1 as a nuclear kinase for p65, since MSK1 associates with p65 in a stimulus‐dependent way and phosphorylates p65 at Ser276. This effect represents, together with phosphorylation of nucleosome components such as histone H3, an essential step leading to selective transcriptional activation of NF‐κB‐dependent gene expression.