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Published online 2 February 2004

Nucleic Acids Research, 2004, Vol. 32, No. 2 719-727
© 2004 Oxford University Press

A new {gamma}-interferon-inducible promoter and splice variants of an anti-angiogenic human tRNA synthetase

Jianming Liu, Eveline Shue, Karla L. Ewalt and Paul Schimmel*

The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC-379, La Jolla, CA 92037, USA

*To whom correspondence should be addressed. Tel: +1 858 784 8970; Fax: +1 858 784 8990; Email: schimmel{at}scripps.edu

Two forms of human tryptophanyl-tRNA synthetase (TrpRS) are produced in vivo through alternative mRNA splicing. The two forms, full-length TrpRS and mini TrpRS, are catalytically active, but are distinguished by the striking anti-proliferative and anti-angiogenic activity specific to mini TrpRS. Here we describe two new splice variants of human TrpRS mRNA. Their production was strongly regulated by {gamma}-interferon (IFN-{gamma}), an anti-proliferative cytokine known to stimulate the expression of other anti-angiogenic factors. A new IFN-{gamma}-sensitive promoter was demonstrated to drive production of these splice variants. In human endothelial cells, both the newly discovered and a previously reported promoter were shown to respond specifically to IFN-{gamma} and not to other cytokines such as tumor necrosis factor-{alpha}, transforming growth factor-ß, interleukin-4 or erythropoietin. In addition, both promoters were stimulated by the ‘downstream’ interferon regulatory factor 1 that, in turn, is known to be regulated by the ‘upstream’ signal transducer and activator of transcription 1{alpha} subunit. Thus, the tandem promoters provide a dual system to regulate expression and alternative splicing of human TrpRS in vivo.


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