Delayed activation of insulin-like growth factor-1 receptor/Src/MAPK/Egr-1 signaling regulates clusterin expression, a pro-survival factor
Delayed activation of insulin-like growth factor-1 receptor/Src/MAPK/Egr-1 signaling regulates clusterin expression, a pro-survival factor
复制标题
DOI：
10.1074/jbc.m412569200
复制
发表时间：
2005-04-08
影响因子：
4.8
通讯作者：
Boothman, DA
中科院分区：
文献类型：
--
作者：
Criswell, T;Beman, M;Boothman, DA
分泌性聚簇蛋白（sCLU）是一种常见的基因毒性应激诱导的促生存基因产物，与衰老、肥胖、心脏病和癌症有关。然而，控制sCLU表达的调控信号转导过程仍未明确。在这里，我们报道了sCLU的诱导是延迟的，在低剂量电离辐射后72小时达到峰值，并且依赖于胰岛素样生长因子- 1的上调以及其受体（分别为IGF- 1和IGF- 1R）的磷酸化依赖性激活。激活的IGF- 1R随后刺激下游的Src- Mek- Erk信号转导级联，最终反激活sCLU表达所需的早期生长反应- 1 （Egr- 1）转录因子。因此，电离辐射暴露导致应激诱导的IGF- 1R-Src-Mek- Erk- Egr- 1信号的激活，该信号调节sCLU促生存级联通路，这对于癌症治疗中的放射耐药很重要。
Secretory clusterin protein ( sCLU) is a general genotoxic stress- induced, pro- survival gene product implicated in aging, obesity, heart disease, and cancer. However, the regulatory signal transduction processes that control sCLU expression remain undefined. Here, we report that induction of sCLU is delayed, peaking 72 h after low doses of ionizing radiation, and is dependent on the up- regulation of insulin- like growth factor- 1 as well as phosphorylation- dependent activation of its receptor ( IGF- 1 and IGF- 1R, respectively). Activated IGF- 1R then stimulates the downstream Src- Mek- Erk signal transduction cascade to ultimately transactivate the early growth response- 1 ( Egr- 1) transcription factor, required for sCLU expression. Thus, ionizing radiation exposure causes stress- induced activation of IGF- 1R-Src-Mek- Erk- Egr- 1 signaling that regulates the sCLU pro- survival cascade pathway, important for radiation resistance in cancer therapy.