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Mol. Cell. Biol., 06 1996, 2814-2822, Vol 16, No. 6
Copyright © 1996, American Society for Microbiology

2-Aminopurine selectively inhibits splicing of tumor necrosis factor alpha mRNA

N Jarrous, F Osman and R Kaempfer
Department of Molecular Virology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

2-Aminopurine (2-AP) inhibits specific kinases that phosphorylate the alpha subunit of eukaryotic translation initiation factor 2. One of these, PKR, is also involved in signal transduction. We show here that 2-AP selectively inhibits expression of tumor necrosis factor alpha (TNF-alpha) mRNA in primary human lymphoid cells. 2-AP does not inhibit transcription of the human TNF-alpha gene, nor does it affect mRNA stability. Instead, the flow of short-lived precursor transcripts into mature TNF-alpha mRNA is blocked. When 2-AP is present during induction, unspliced TNF-alpha precursor transcripts accumulate at the expense of mRNA. Using RNase protection analysis with genomic probes for different exon-intron junctions, we show that 2-AP blocks splicing of TNF-alpha mRNA. Neither the TNF-beta nor the interleukin-1 beta gene shows such regulation. 2-AP also inhibits splicing of precursor RNA transcribed from an exogenous human TNF-alpha gene. Sequences within this gene thus confer sensitivity to 2-AP. Yet, control is not exerted at a specific splice site. Our results reveal the involvement of a 2-AP- sensitive component, expressed in functional form before induction, in the splicing of TNF-alpha mRNA.


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