Downregulation of FUSE-binding protein and c-myc by tRNA synthetase cofactor p38 is required for lung cell differentiation
Downregulation of FUSE-binding protein and c-myc by tRNA synthetase cofactor p38 is required for lung cell differentiation
复制标题
DOI：
10.1038/ng1182
复制
发表时间：
2003-07-01
期刊：
影响因子：
30.8
通讯作者：
Kim, S
中科院分区：
文献类型：
--
作者：
Kim, MJ;Park, BJ;Kim, S
P38与一个大分子tRNA合成酶复合体(1)相关。它作为复合体的支架具有重要作用，而小鼠体内p38基因的破坏会导致新生儿死亡(2)。在这里，我们研究了p38突变小鼠致死的分子机制。P38基因缺陷小鼠表现出肺分化缺陷和呼吸窘迫综合征。P38被发现与c-myc的转录激活剂融合结合蛋白(FBP)相互作用。P38的结合刺激泛素化和FBP的降解，导致c-myc下调，而c-myc是功能肺泡II型细胞分化所必需的。转化生长因子-β诱导p38的表达，并促进其向细胞核转位，以调节FBP和c-myc。因此，这项工作确定了一个新的p38活性，作为转化生长因子-β信号的中介，以及它在肺分化过程中控制c-myc的功能重要性。
p38 is associated with a macromolecular tRNA synthetase complex(1). It has an essential role as a scaffold for the complex, and genetic disruption of p38 in mice causes neonatal lethality(2). Here we investigated the molecular mechanisms underlying lethality of p38-mutant mice. p38-deficient mice showed defects in lung differentiation and respiratory distress syndrome. p38 was found to interact with FUSE-binding protein (FBP), a transcriptional activator of c-myc(3). Binding of p38 stimulated ubiquitination and degradation of FBP, leading to downregulation of c-myc, which is required for differentiation of functional alveolar type II cells. Transforming growth factor-beta (TGF-beta) induced p38 expression and promoted its translocation to nuclei for the regulation of FBP and c-myc. Thus, this work identified a new activity of p38 as a mediator of TGF-beta signaling and its functional importance in the control of c-myc during lung differentiation.