A cis-acting element in the 3'-untranslated region of human TNF-α mRNA renders splicing dependent on the activation of protein kinase PKR

Farhat Osman, Nayef Jarrous, Yitzhak Ben-Asouli, Raymond Kaempfer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

We report a role for the 3'-untranslated region in control of mRNA splicing and show that human TNF-α 3' UTR harbors a cis- acting element that renders splicing of precursor transcripts dependent on activation of PKR, the RNA-activated protein kinase that phosphorylates eukaryotic initiation factor 2 (eIF2). When this element, designated 2-APRE, is present, splicing becomes sensitive to inhibition by the PKR inhibitor, 2-aminopurine, or by coexpression of transdominant-negative mutant PKR. Our results reveal that activation of PKR is required for splicing of mRNA when precursor transcripts contain the 2-APRE and that increased expression of wild-type PKR enhances their splicing efficiency. Thus, PKR responds as trans-acting factor to the 2-APRE. 2-APRE RNA forms a stable, 17-bp stem-loop structure and strongly activates PKR in vitro, inducing eIF2α phosphorylation. Despite its ability to activate PKR during splicing, the 2-APRE within the 3' UTR does not affect translation efficiency of the resulting TNF-α mRNA in transfected cells. PKR and the 3' UTR thus interact during mRNA splicing to confer a novel type of regulation on expression of the TNF-α gene.

Original languageAmerican English
Pages (from-to)3280-3293
Number of pages14
JournalGenes and Development
Volume13
Issue number24
DOIs
StatePublished - 15 Dec 1999

Bibliographical note

Funding Information:
We would like to thank Craig Foltz for establishing the connection among us. A. G. M. would like to thank E. Dwek for useful discussions. J. A. M. is supported by a postdoctoral fellowship from Ministerio de Educación y Cultura, Spain. We also thank the anonymous referee for correcting an error in the first version of our manuscript.

Keywords

  • 3'- untranslated region
  • Cis-acting RNA element
  • Protein kinase PKR
  • Splicing
  • Tumor necrosis factor

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