Ming X F, Stoecklin G, Lu M, Looser R, Moroni C
Institute for Medical Microbiology, University of Basel, Basel, Switzerland.
Mol Cell Biol. 2001 Sep;21(17):5778-89. doi: 10.1128/MCB.21.17.5778-5789.2001.
AU-rich elements (ARE) present in the 3' untranslated regions of many cytokines and immediate-early genes are responsible for targeting the transcripts for rapid decay. We present evidence from cotransfection experiments in NIH 3T3 cells that two signaling pathways, one involving phosphatidylinositol 3-kinase (PI3-K), and one involving the p38 mitogen-activated protein kinase (MAPK), lead to stabilization of interleukin-3 mRNA in parallel. Stabilization mediated by either of the two pathways was antagonized by tristetraprolin (TTP), an AU-binding protein known to promote constitutive decay of ARE-containing transcripts. Remarkably, the stabilizing AU-binding protein HuR, in collaboration with p38 MAPK but not with PI3-K, could overcome the destabilizing effect of TTP. These data argue that the stabilizing kinases PI3-K and p38 MAPK do not act through direct inactivation of TTP but via activating pathway-specific stabilizing AU-binding proteins. Our data suggest an integrated model of mRNA turnover control, where stabilizing (HuR) and destabilizing (TTP) AU-binding proteins compete and where the former are under the positive control of independent phosphokinase signaling pathways.
许多细胞因子和即早基因的3'非翻译区中存在的富含AU元件（ARE）负责将转录本靶向快速降解。我们通过在NIH 3T3细胞中的共转染实验提供证据，表明两条信号通路，一条涉及磷脂酰肌醇3激酶（PI3-K），另一条涉及p38丝裂原活化蛋白激酶（MAPK），可并行导致白细胞介素-3 mRNA的稳定。两条通路中任何一条介导的稳定作用都被三链四脯氨酸（TTP）拮抗，TTP是一种已知可促进含ARE转录本组成性降解的AU结合蛋白。值得注意的是，稳定的AU结合蛋白HuR与p38 MAPK而非PI3-K协作，可克服TTP的去稳定作用。这些数据表明，稳定激酶PI3-K和p38 MAPK并非通过直接使TTP失活起作用，而是通过激活特定通路的稳定AU结合蛋白起作用。我们的数据提示了一种mRNA周转控制的整合模型，其中稳定（HuR）和去稳定（TTP）的AU结合蛋白相互竞争，且前者受独立磷酸激酶信号通路的正向调控。
