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J Biol Chem. 2010 Apr 23;285(17):12490-6. doi: 10.1074/jbc.M109.091660. Epub 2010 Jan 29.

Alternative splicing factor/splicing factor 2 regulates the expression of the zeta subunit of the human T cell receptor-associated CD3 complex.

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  • 1Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.

Abstract

T cells from patients with systemic lupus erythematosus express decreased levels of the T cell receptor-associated CD3 zeta chain, a feature directly linked to their aberrant function. The decrease in CD3zeta protein expression is in part due to decreased levels of functional wild type isoform of the 3'-untranslated region (UTR) of CD3zeta mRNA with concomitant increased levels of an unstable alternatively spliced isoform. In order to identify factors involved in the post-transcriptional regulation of CD3zeta, we performed mass spectrometric analysis of Jurkat T cell nuclear proteins "pulled down" by a CD3zeta 3'-UTR oligonucleotide, which identified the splicing protein alternative splicing factor/splicing factor 2 (ASF/SF2). We show for the first time that ASF/SF2 binds specifically to the 3'-UTR of CD3zeta and regulates expression of CD3zeta protein by limiting the production of the alternatively spliced isoform. During activation of human T cells, an increase in the wild type CD3zeta mRNA is associated with increased expression of ASF/SF2. Finally, we show a significant correlation between ASF/SF2 and CD3zeta protein levels in T cells from systemic lupus erythematosus patients. Thus, our results identify ASF/SF2 as a novel factor in the regulation of alternative splicing of the 3'-UTR of CD3zeta and protein expression in human T cells.

PMID:
20118245
[PubMed - indexed for MEDLINE]
PMCID:
PMC2857141
Free PMC Article

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