Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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Originally published online as doi:10.1189/jlb.0907641 on January 24, 2008

Published online before print January 24, 2008
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(Journal of Leukocyte Biology. 2008;83:982-990.)
© 2008 by Society for Leukocyte Biology

Nitric oxide-p38 MAPK signaling stabilizes mRNA through AU-rich element-dependent and -independent mechanisms

Shuibang Wang, Jianhua Zhang, Yi Zhang, Steven Kern and Robert L. Danner1

Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

1 Correspondence: Critical Care Medicine Department, Bldg. 10, Rm. 2C145, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. E-mail: rdanner{at}cc.nih.gov

Regulation of mRNA stability by p38 MAPK has been linked to adenosine-uridine-rich elements (AURE) within the 3'-untranslated region (3'UTR) of mRNA. Using microarrays, we previously found that AURE-containing mRNA is over-represented among transcripts up-regulated by NO•, an activator of p38 MAPK. Here, we investigated NO•-induced mRNA stabilization of specific AURE-containing genes to determine the sequence specificity and protein-binding interactions associated with this effect. IL-8, TNF-{alpha}, and p21/Waf1 3'UTRs were inserted into a luciferase (LUC) reporter gene system and found to decrease LUC activity and mRNA half-life in transfected THP-1 cells. The inhibitory effect of these 3'UTRs on LUC expression inversely correlated with the number of AUUUA motifs. Sequence truncation of the IL-8 3'UTR revealed that two segments, one with AURE sites and another without, contributed to mRNA destabilization. NO• activation of p38 MAPK increased LUC activity and mRNA half-life for reporter constructs that contained either of these IL-8 3'UTR segments. AURE-dependent and -independent NO• effects were blocked by p38 MAPK inhibition, and AURE-dependent effects were also blocked by site-directed mutagenesis of AUUUA sites. Two proteins, HuR and heterogeneous nuclear ribonucleoprotein A0, were identified, which bound to the AURE-containing region of exogenous and endogenous IL-8 mRNA in a NO•-p38 MAPK-dependent manner. These results demonstrate that NO•-p38 MAPK signaling can stabilize mRNA via AURE-dependent and -independent mechanisms.

Key Words: signal transduction • post-transcriptional gene regulation • HuR • hnRNP A0






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