Bollig Frank, Winzen Reinhard, Kracht Michael, Ghebremedhin Beniam, Ritter Birgit, Wilhelm Arno, Resch Klaus, Holtmann Helmut
Institute of Pharmacology, Medical School Hannover, Germany.
Eur J Biochem. 2002 Dec;269(23):5830-9. doi: 10.1046/j.1432-1033.2002.03300.x.
mRNA stabilization plays an important role in the changes in protein expression initiated by inducers of inflammation or direct cell stress such as UV light. This study provides evidence that stabilization in response to UV light differs from that induced by proinflammatory stimuli such as bacterial lipopolysaccharide or interleukin (IL)-1. Firstly, UV-induced stabilization is independent of the p38 MAP kinase pathway, which has previously been shown to mediate stabilization induced by IL-1 or lipopolysaccharide. UV-induced mRNA stabilization was insensitive to the dominant negative forms of p38 MAP kinase and its substrate MAP kinase-activated protein kinase 2 (MK2), or to the p38 MAP kinase inhibitor SB 203580, demonstrating that it occurs through a different signaling mechanism. Secondly, UV-induced stabilization exhibits a different transcript selectivity. Activation of the p38 MAP kinase pathway, by expressing active MAP kinase kinase 6, induced stabilization only of transcripts containing AU-rich elements. UV light also induced stabilization of transcripts lacking AU-rich elements. This effect could not be mimicked by expressing MEKK1, an upstream activator of the p38, JNK, ERK and NF-kappaB pathways. UV light also stabilized endogenous histone mRNA, which lacks AU-rich elements and a poly(A) tail. This effect was not mimicked by active MAP kinase kinase 6 and not sensitive to a p38 MAP kinase inhibitor. This suggests that UV light induces stabilization through a mechanism that is independent of p38 MAP kinase and affects a broad spectrum of mRNAs.
mRNA 稳定性在由炎症诱导剂或直接细胞应激（如紫外线）引发的蛋白质表达变化中起重要作用。本研究提供的证据表明，对紫外线的稳定性反应不同于由促炎刺激（如细菌脂多糖或白细胞介素 (IL)-1）诱导的稳定性反应。首先，紫外线诱导的稳定性独立于 p38 MAP 激酶途径，先前已证明该途径介导由 IL-1 或脂多糖诱导的稳定性。紫外线诱导的 mRNA 稳定性对 p38 MAP 激酶及其底物 MAP 激酶激活的蛋白激酶 2 (MK2) 的显性负性形式不敏感，或对 p38 MAP 激酶抑制剂 SB 203580 不敏感，表明它通过不同的信号传导机制发生。其次，紫外线诱导的稳定性表现出不同的转录本选择性。通过表达活性 MAP 激酶激酶 6 激活 p38 MAP 激酶途径，仅诱导含有富含 AU 元件的转录本的稳定性。紫外线也诱导缺乏富含 AU 元件的转录本的稳定性。表达 MEKK1（p38、JNK、ERK 和 NF-κB 途径的上游激活剂）无法模拟这种效应。紫外线还稳定了内源性组蛋白 mRNA，其缺乏富含 AU 元件和 poly(A) 尾巴。这种效应不能被活性 MAP 激酶激酶 6 模拟，并且对 p38 MAP 激酶抑制剂不敏感。这表明紫外线通过一种独立于 p38 MAP 激酶的机制诱导稳定性，并影响广泛的 mRNA。
