Schouten G J, Vertegaal A C, Whiteside S T, Israël A, Toebes M, Dorsman J C, van der Eb A J, Zantema A
Laboratory for Molecular Carcinogenesis, Sylvius Laboratories, Leiden University, The Netherlands.
EMBO J. 1997 Jun 2;16(11):3133-44. doi: 10.1093/emboj/16.11.3133.
The activity of transcription factor NFkappaB is regulated by its subcellular localization. In most cell types, NFkappaB is sequestered in the cytoplasm due to binding of the inhibitory protein IkappaB alpha. Stimulation of cells with a wide variety of agents results in degradation of IkappaB alpha which allows translocation of NFkappaB to the nucleus. Degradation of IkappaB alpha is triggered by phosphorylation of two serine residues, i.e. Ser32 and Ser36, by as yet unknown kinases. Here we report that the mitogen-activated 90 kDa ribosomal S6 kinase (p90rsk1) is an IkappaB alpha kinase. p90rsk1 phosphorylates IkappaB alpha at Ser32 and it physically associates with IkappaB alpha in vivo. Moreover, when the function of p90rsk1 is impaired by expression of a dominant-negative mutant, IkappaB alpha degradation in response to mitogenic stimuli, e.g. 12-O-tetradecanoylphorbol 13-acetate (TPA), is inhibited. Finally, NFkappaB cannot be activated by TPA in cell lines that have low levels of p90rsk1. We conclude that p90rsk1 is an essential kinase required for phosphorylation and subsequent degradation of IkappaB alpha in response to mitogens.
转录因子NFκB的活性受其亚细胞定位的调控。在大多数细胞类型中，由于抑制性蛋白IκBα的结合，NFκB被隔离在细胞质中。用多种试剂刺激细胞会导致IκBα降解，从而使NFκB易位至细胞核。IκBα的降解是由两个丝氨酸残基（即Ser32和Ser36）被未知激酶磷酸化所触发的。在此我们报告，丝裂原活化的90 kDa核糖体S6激酶（p90rsk1）是一种IκBα激酶。p90rsk1使IκBα的Ser32位点磷酸化，并且在体内与IκBα发生物理结合。此外，当p90rsk1的功能因显性负性突变体的表达而受损时，对促有丝分裂刺激（如12-O-十四烷酰佛波醇-13-乙酸酯（TPA））的反应中IκBα的降解受到抑制。最后，在p90rsk1水平较低的细胞系中，TPA无法激活NFκB。我们得出结论，p90rsk1是有丝分裂原刺激下IκBα磷酸化及随后降解所必需的激酶。
