ENDOTOXIN-RESPONSIVE SEQUENCES CONTROL CACHECTIN TUMOR NECROSIS FACTOR BIOSYNTHESIS AT THE TRANSLATIONAL LEVEL
ENDOTOXIN-RESPONSIVE SEQUENCES CONTROL CACHECTIN TUMOR NECROSIS FACTOR BIOSYNTHESIS AT THE TRANSLATIONAL LEVEL
复制标题
DOI：
10.1084/jem.171.2.465
复制
发表时间：
1990-02-01
影响因子：
15.3
通讯作者：
BEUTLER, B
中科院分区：
文献类型：
--
作者：
HAN, J;BROWN, T;BEUTLER, B
恶病质素/肿瘤坏死因子（cachectin/TNF）的生物合成在很大程度上受转录后水平的调控。细菌内毒素能强烈诱导恶病质素/肿瘤坏死因子的产生，它似乎是通过改变巨噬细胞的细胞质环境来引发至少一些效应。先前已表明，存在于众多细胞因子和原癌基因中的3′ - 非翻译区的TTATTTAT元件能够抑制含有该元件的mRNA分子的翻译。我们利用构建体，其中氯霉素乙酰转移酶（CAT）编码序列后接恶病质素/肿瘤坏死因子3′ - 非翻译区的不同片段，现在证明恶病质素/肿瘤坏死因子mRNA中存在的下游序列足以介导在受到内毒素激活时氯霉素乙酰转移酶合成超过200倍的诱导。氯霉素乙酰转移酶活性的诱导不是由于细胞质mRNA浓度的改变，而是由于翻译效率的显著提高。对内毒素的反应代表“去抑制”，并且主要是由具有翻译抑制作用的TTATTTAT元件与必要的侧翼序列协同作用所赋予的。
The biosynthesis of cachectin/TNF is largely regulated at a post-transcriptional level. Bacterial endotoxin, which strongly induces cachectin/TNF production, thus seems to elicit at least some of its effects by altering the macrophage cytoplasmic milieu. It has previously been shown that the 3''-untranslated TTATTTAT element present in numerous cytokines and proto-oncogenes is capable of repressing the translation of mRNA molecules in which it is represented. Using constructs in which the CAT coding sequence is follwed by varying segments of the cachectin/TNF 3''-untranslated region, we now demonstrate that downstream sequences present in the cachectin/TNF mRNA are sufficient to mediate > 200-fold induction of CAT synthesis in response to activation by endotoxin. Induction of CAT activity is not attributable to a change in cytoplasmic mRNA concentration, but to a marked enhancement of translational efficiency. The response to endotoxin represents "derepression," and is conferred chiefly by the translationally repressive TTATTTAT element, acting in concert essential flanking sequences.