title: Nuclear translocation of MEK1 triggers a complex T cell response through the corepressor silencing mediator of retinoid and thyroid hormone receptor.
abstract: MEK1 phosphorylates ERK1/2 and regulates T cell generation, differentiation, and function. MEK1 has recently been shown to translocate to the nucleus. Its nuclear function is largely unknown. By studying human CD4 T cells, we demonstrate that a low level of MEK1 is present in the nucleus of CD4 T cells under basal conditions. T cell activation further increases the nuclear translocation of MEK1. MEK1 interacts with the nuclear receptor corepressor silencing mediator of retinoid and thyroid hormone receptor (SMRT). MEK1 reduces the nuclear level of SMRT in an activation-dependent manner. MEK1 is recruited to the promoter of c-Fos upon TCR stimulation. Conversely, SMRT is bound to the c-Fos promoter under basal conditions and is removed upon TCR stimulation. We examined the role of SMRT in regulation of T cell function. Small interfering RNA-mediated knockdown of SMRT results in a biphasic effect on cytokine production. The production of the cytokines IL-2, IL-4, IL-10, and IFN-γ increases in the early phase (8 h) and then decreases in the late phase (48 h). The late-phase decrease is associated with inhibition of T cell proliferation. The late-phase inhibition of T cell activation is, in part, mediated by IL-10 that is produced in the early phase and, in part, by β-catenin signaling. Thus, we have identified a novel nuclear function of MEK1. MEK1 triggers a complex pattern of early T cell activation, followed by a late inhibition through its interaction with SMRT. This biphasic dual effect most likely reflects a homeostatic regulation of T cell function by MEK1.
authors.affiliation: Division of Allergy and Immunology, Department of Medicine, National Jewish Health, Denver, CO 80206, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.forename: Chaoyu
authors.initials: C
authors.lastname: Chen
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Liang
authors.forename: Mohammad Zunayet
authors.initials: MZ
authors.lastname: Karim
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Gorska
authors.forename: Rafeul
authors.initials: R
authors.lastname: Alam
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D020868:Gene Silencing / Q000276:immunology; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D056971:Nuclear Receptor Co-Repressor 1 / Q000502:physiology*; D056985:Nuclear Receptor Co-Repressor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism
chemical_list: D006131:Growth Inhibitors; C539130:NCOR2 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D016760:Proto-Oncogene Proteins c-fos; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human