Post-transcriptional regulation of RNase-L expression is mediated by the 3'-untranslated region of its mRNA
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RNase-L mediates critical cellular functions including antiviral, pro-apoptotic, and tumor suppressive activities; accordingly, its expression must be tightly regulated. Little is known about the control of RNASEL expression; therefore, we examined the potential regulatory role of a conserved 3'-untranslated region (3'-UTR) in its mRNA. The 3'-UTR mediated a potent decrease in the stability of RNase-L mRNA, and of a chimeric beta-globin-3'-UTR reporter mRNA. AU-rich elements (AREs) are cis-acting regulatory regions that modulate mRNA stability. Eight AREs were identified in the RNase-L 3'-UTR, and deletion analysis identified positive and negative regulatory regions associated with distinct AREs. In particular, AREs 7 and 8 served a strong positive regulatory function. HuR is an ARE-binding protein that stabilizes ARE-containing mRNAs, and a predicted HuR binding site was identified in the region comprising AREs 7 and 8. Co-transfection of HuR and RNase-L enhanced RNase-L expression and mRNA stability in a manner that was dependent on this 3'-UTR region. Immunoprecipitation demonstrated that RNase-L mRNA associates with a HuR containing complex in intact cells. Activation of endogenous HuR by cell stress, or during myoblast differentiation, increased RNase-L expression, suggesting that RNase-L mRNA is a physiologic target for HuR. HuR-dependent regulation of RNase-L enhanced its antiviral activity demonstrating the functional significance of this regulation. These findings identify a novel mechanism of RNase-L regulation mediated by its 3'-UTR.
Original language | English |
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Journal | The Journal of Biological Chemistry |
Volume | 282 |
Issue number | 11 |
Pages (from-to) | 7950-60 |
Number of pages | 11 |
ISSN | 0021-9258 |
DOIs | |
Publication status | Published - 16 Mar 2007 |
Externally published | Yes |
- 3' Untranslated Regions, Antigens, Surface, Antiviral Agents, Apoptosis, Base Sequence, Cell Differentiation, Endoribonucleases, Gene Expression Regulation, Enzymologic, Genes, Reporter, Globins, HeLa Cells, Hu Paraneoplastic Encephalomyelitis Antigens, Humans, Molecular Sequence Data, Myoblasts, RNA, Messenger, RNA-Binding Proteins
Research areas
ID: 97140193