The cyclic AMP response element modulator regulates transcription of the TCR zeta-chain.
Systemic lupus erythematosus T cells display decreased amounts of TCR zeta mRNA that results in part from limited binding of the transcriptional enhancer Elf-1 to the TCR zeta promoter. We have identified a new cis-binding site for the cAMP response element (CRE) modulator (CREM) on the TCR zeta promoter, centered on the -390 nucleotide. Transfection of T cells with an antisense CREM alpha plasmid reduced the binding of CREM to the TCR zeta promoter, as shown by chromatin and reporter chromatin immunoprecipitation assays, and enhanced the production of TCR zeta mRNA and protein. Mutagenesis of the -390 CRE site prevented the binding of CREM to the TCR zeta promoter. The mechanism of CREM-mediated repression appears to be chromatin dependent, because antisense CREM promotes the acetylation of histones on the TCR zeta promoter. Finally, we established an enhanced binding of CREM to the TCR zeta-chain promoter in systemic lupus erythematosus cells compared with control T cells. Our studies demonstrate that CREM alpha binds to the TCR zeta promoter and repress its activity.
Tenbrock
Klaus
K
Department of Pediatrics, Division of Rheumatology, University Hospital, Muenster, Germany. ktenbroc@uni-muenster.de
Kyttaris
Vasileios C
VC
Ahlmann
Martina
M
Ehrchen
Jan Mauno
JM
Tolnay
Mate
M
Melkonyan
Harutyun
H
Mawrin
Christian
C
Roth
Johannes
J
Sorg
Clemens
C
Juang
Yuang-Taung
YT
Tsokos
George C
GC
D042002:Chromatin Assembly and Disassembly; D051786:Cyclic AMP Response Element Modulator / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C054979:antigen T cell receptor, zeta chain; D051786:Cyclic AMP Response Element Modulator