Published online 6 June 2006
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Nitric oxide activation of Erk1/2 regulates the stability and translation of mRNA transcripts containing CU-rich elements
Critical Care Medicine Department, Clinical Center, National Institutes of Health Bethesda, MD 20892, USA 1 Mathematical and Statistical Computing Laboratory, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health Bethesda, MD 20892, USA
*To whom correspondence should be addressed. Tel: +1 301 496 9320; Fax: +1 301 402 1213; Email: rdanner{at}cc.nih.gov
Received March 1, 2006. Accepted May 5, 2006.
Nitric oxide (NO•) can stabilize mRNA by activating p38 mitogen-activated protein kinase (MAPK). Here, transcript stabilization by NO• was investigated in human THP-1 cells using microarrays. After LPS pre-stimulation, cells were treated with actinomycin D and then exposed to NO• without or with the p38 MAPK inhibitor SB202190 (SB). The decay of 220 mRNAs was affected; most were stabilized by NO•. Unexpectedly, SB often enhanced rather than antagonized transcript stability. NO• activated p38 MAPK and Erk1/2; SB blocked p38 MAPK, but further activated Erk1/2. RT–PCR confirmed that NO• and SB could additively stabilize certain mRNA transcripts, an effect abolished by Erk1/2 inhibition. In affected genes, these responses were associated with CU-rich elements (CURE) in 3'-untranslated regions (3'-UTR). NO• stabilized the mRNA of a CURE-containing reporter gene, while repressing translation. Dominant-negative Mek1, an Erk1/2 inhibitor, abolished this effect. NO• similarly stabilized, but blocked translation of MAP3K7IP2, a natural CURE-containing gene. NO• increased hnRNP translocation to the cytoplasm and binding to CURE. Over-expression of hnRNP K, like NO•, repressed translation of CURE-containing mRNA. These findings define a sequence-specific mechanism of NO•-triggered gene regulation that stabilizes mRNA, but represses translation.
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