Involvement of CREB-regulated transcription coactivators (CRTC) in transcriptional activation of steroidogenic acute regulatory protein (Star) by ACTH.
Involvement of CREB-regulated transcription coactivators (CRTC) in transcriptional activation of steroidogenic acute regulatory protein (Star) by ACTH.
复制标题
CREB 调节的转录共激活因子 (CRTC) 参与 ACTH 对类固醇生成急性调节蛋白 (Star) 的转录激活。
DOI：
10.1016/j.mce.2019.110612
复制
发表时间：
2020
影响因子：
4.1
通讯作者：
Smith LIF
中科院分区：
文献类型：
--
作者：
Smith LIF
活体研究表明，CREB调节的转录共激活因子(CRTC)2参与了ACTH诱导的关键类固醇生成蛋白-类固醇生成急性调节(STAR)的转录。本研究使用两个ACTH反应的肾上腺皮质细胞系，研究CRTC在启动转录中的作用。在这里，我们发现ACTH诱导的Star初级转录本，或异核RNA(HnRNA)，平行于CRTC的3个亚型：CRTC1，CRTC2和CRTC3的核水平快速增加。此外，ACTH促进了STAR启动子对CRTC2和CRTC3的招募，而CRTC3或CRTC2的siRNA敲除减弱了ACTH诱导的StarhnRNA的增加。利用PKA、MAP和钙调神经磷酸酶的药物抑制剂，我们发现ACTH对启动转录和CRTC核转位的影响主要依赖于PKA途径。这些数据为CRTC2和CRTC3参与ACTH激活启动转录提供了证据，并且PKA/CRTC依赖的通路是调控启动转录的多因素机制的一部分。
Studiesin vivohave suggested the involvement of CREB-regulated transcription coactivator (CRTC)2 on ACTH-induced transcription of the key steroidogenic protein, Steroidogenic Acute Regulatory (StAR). The present study uses two ACTH-responsive adrenocortical cell lines, to examine the role of CRTC onStartranscription. Here we show that ACTH-inducedStarprimary transcript, or heteronuclear RNA (hnRNA), parallels rapid increases in nuclear levels of the 3 isoforms of CRTC; CRTC1, CRTC2 and CRTC3. Furthermore, ACTH promotes recruitment of CRTC2 and CRTC3 by theStarpromoter and siRNA knockdown of either CRTC3 or CRTC2 attenuates the increases in ACTH-inducedStarhnRNA. Using pharmacological inhibitors of PKA, MAP kinase and calcineurin, we show that the effects of ACTH onStartranscription and CRTC nuclear translocation depend predominantly on the PKA pathway. The data provides evidence that CRTC2 and CRTC3, contribute to activation ofStartranscription by ACTH, and that PKA/CRTC-dependent pathways are part of the multifactorial mechanisms regulatingStartranscription.