title: Transcriptional activation of the cAMP-responsive modulator promoter in human T cells is regulated by protein phosphatase 2A-mediated dephosphorylation of SP-1 and reflects disease activity in patients with systemic lupus erythematosus.
abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with numerous abnormalities recorded at the cellular, molecular, and genetic level. Expression of the basic leucine zipper transcription factor cAMP-responsive element modulator (CREM)α was reported to be abnormally increased in T cells from SLE patients. CREMα suppresses IL-2 and T cell receptor ζ chain gene transcription by direct binding to the respective promoters. Here, we show that increased CREM expression is the result of enhanced promoter activity. DNA binding analyses reveal direct binding of transcription factor specificity protein-1 (SP-1) to the CREM promoter resulting in enhanced transcriptional activity and increased CREM expression. Protein phosphatase 2A is known to activate SP-1 through dephosphorylation at its serine residue 59. Our results show that nuclei from SLE T cells contain lower levels of Ser(59)-phosphorylated SP-1 protein and a stronger SP-1 binding to the CREM promoter. We conclude that protein phosphatase 2A accounts for enhanced SP-1 dephosphorylation at Ser(59) in SLE T cells. More importantly, CREM promoter activity mirrors reliably disease activity in SLE patients, underscoring its potential role as a biomarker for the prediction of flares in SLE patients.
authors.affiliation: Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Yuang-Taung
authors.initials: YT
authors.lastname: Juang
authors.forename: Thomas
authors.initials: T
authors.lastname: Rauen
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Ichinose
authors.forename: Konrad
authors.initials: K
authors.lastname: Benedyk
authors.forename: Klaus
authors.initials: K
authors.lastname: Tenbrock
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010766:Phosphorylation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D015415:Biomarkers; C508594:IL2 protein, human; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D016329:Sp1 Transcription Factor; D051786:Cyclic AMP Response Element Modulator; D054648:Protein Phosphatase 2