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mRNA Are Regulated by the Adenosine-Uridine-Rich Elements in Splice-Deleted 3' Untranslated Region of -Chain1,2
Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910, and Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
Systemic lupus erythematosus (SLE) T cells display reduced expression of TCR 
protein. Recently, we reported that in SLE T cells, the residual TCR protein is predominantly derived from an alternatively spliced form that undergoes splice deletion of 562 nt (from 672 to 1233 bases) within the 3' untranslated region (UTR) of TCR mRNA. The stability and translation of the alternatively spliced form of TCR mRNA are low compared with that of the wild-type TCR mRNA. We report that two adenosine-uridine-rich sequence elements (AREs), defined by the splice-deleted 3' UTR region, but not an ARE located upstream are responsible for securing TCR mRNA stability and translation. The stabilizing effect of the splice-deleted region-defined AREs extended to the luciferase mRNA and was not cell type-specific. The findings demonstrate distinct sequences within the splice-deleted region 672 to 1233 of the 3' UTR, which regulate the transcription, mRNA stability, and translation of TCR mRNA. The absence of these sequences represents a molecular mechanism that contributes to altered TCR -chain expression in lupus.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study is supported by the National Institutes of Health Grants R01 AI42269 and R01 AR39501.
2 The opinions and assertions contained herein are private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
3 B.C. and S.K. contributed equally to this work.
4 Address correspondence and reprint requests to Dr. George C. Tsokos, Department of Cellular Injury, Walter Reed Army Institute of Research, Building 503, Room 1A32, 503 Robert Grant Avenue, Silver Spring, MD 20910. E-mail address: gtsokos{at}usa.net
5 Abbreviations used in this paper: SLE, systemic lupus erythematosus; ARE, AU-rich element; WT, wild type; UTR, untranslated region; CS, conserved sequence; m, mutant (in mARE1, mARE2, and mCS).
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