title: c-Jun and Ets2 proteins regulate expression of spleen tyrosine kinase in T cells.
abstract: Effector T cells and T cells from patients with systemic lupus erythematosus (SLE) express increased levels of the spleen tyrosine kinase (Syk). Syk binds to the T cell receptor (TCR)-CD3 complex and transduces the TCR-mediated signal in the cell more efficiently than the canonical CD3ζ chain. The reasons for the increased expression of Syk are unclear. In the present study, we found that Syk is regulated by the transcription factor c-Jun in cooperation with Ets2. c-Jun and Ets2 bound to the SYK promoter in close proximity and increased the promoter activity in a specific manner. Disruption of c-Jun and Ets2 expression by siRNA resulted in decreased expression of Syk. Overexpression of c-Jun but not Ets2 resulted in increase in Syk protein. c-Jun and Ets2 co-immunoprecipitated and had an additive effect on Syk expression. c-Jun-driven SYK promoter activation showed a similar pattern in B cells; however, as expected, basal promoter activity was much higher in B cells as compared with T cells. Overexpression of c-Jun led to increase in intracytoplasmic calcium flux following TCR stimulation. Moreover, we found that SLE T cells had increased levels of c-Jun at baseline and phosphorylated c-Jun upon activation. Finally, disruption of c-Jun and Ets2 in SLE T cells resulted in a decrease in calcium flux upon TCR stimulation. In conclusion, c-Jun in cooperation with Ets2 increases the expression of Syk and contributes to Syk-mediated heightened calcium responses in SLE T cells.
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Debjani
authors.initials: D
authors.lastname: Ghosh
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
authors.forename: Vasileios C
authors.initials: VC
authors.lastname: Kyttaris
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000201:enzymology / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D020013:Calcium Signaling; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D050787:Proto-Oncogene Protein c-ets-2 / Q000378:metabolism / Q000502:physiology*; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000201:enzymology* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C494069:ETS2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D050787:Proto-Oncogene Protein c-ets-2; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D048031:JNK Mitogen-Activated Protein Kinases