Negative feedback regulation of MKK6 mRNA stability by p38α mitogen-activated protein kinase
Negative feedback regulation of MKK6 mRNA stability by p38α mitogen-activated protein kinase
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DOI：
10.1128/mcb.23.1.370-381.2003
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发表时间：
2003-01-01
影响因子：
5.3
通讯作者：
Nebreda, AR
中科院分区：
文献类型：
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作者：
Ambrosino, C;Mace, G;Nebreda, AR
p38有丝分裂原活化蛋白（MAP）激酶在调节细胞对各种应激的反应中发挥重要作用。最丰富和广泛表达的p38 MAP激酶是p38 α，其也可以控制几种细胞类型的增殖、分化和存活。在这里，我们表明，在p38 α（-/-）敲除小鼠和培养的细胞中，p38 α的缺乏与其上游激活剂之一，MAP激酶激酶MKK 6的上调相关。相反，p38激活剂MKK 3和MKK 4的表达水平在p38 α缺陷细胞中不受影响。MKK 6蛋白浓度的增加与p38 α（-/-）细胞中MKK 6 mRNA的量增加相关。p38 α的药理学抑制也上调HEK 293细胞中的MKK 6 mRNA水平。相反，将p38 α重新引入p38 α-/-细胞中会将MKK 6蛋白和mRNA的水平降低到野生型细胞中发现的正常水平。此外，我们发现MKK 6 mRNA在p38 α-/-细胞中更稳定，并且该mRNA的3 '非翻译区可以以p38 α依赖的方式差异调节lacZ报告基因的稳定性。我们的数据表明，p38 α可以负调节MKK 6 mRNA的稳定性，从而控制其上游激活剂之一的稳态浓度。
p38 mitogen-activated protein (MAP) kinases play an important role in the regulation of cellular responses to all kinds of stresses. The most abundant and broadly expressed p38 MAP kinase is p38alpha, which can also control the proliferation, differentiation, and survival of several cell types. Here we show that the absence of p38alpha correlates with the up-regulation of one of its upstream activators, the MAP kinase kinase MKK6, in p38alpha(-/-) knockout mice and in cultured cells derived from them. In contrast, the expression levels of the p38 activators MKK3 and MKK4 are not affected in p38alpha-deficient cells. The increase in MKK6 protein concentration correlates with increased amounts of MKK6 mRNA in the p38alpha(-/-) cells. Pharmacological inhibition of p38alpha also up-regulates MKK6 mRNA levels in HEK293 cells. Conversely, reintroduction of p38alpha into p38alpha-/- cells reduces the levels of MKK6 protein and mRNA to the normal levels found in wild-type cells. Moreover, we show that the MKK6 mRNA is more stable in p38alpha-/- cells and that the 3'untranslated region of this mRNA can differentially regulate the stability of the lacZ reporter gene in a p38alpha-dependent manner. Our data indicate that p38alpha can negatively regulate the stability of the MKK6 mRNA and thus control the steady-state concentration of one of its upstream activators.