Oxytocin Regulates Stress-Induced Crf Gene Transcription through CREB-Regulated Transcription Coactivator 3
Oxytocin Regulates Stress-Induced Crf Gene Transcription through CREB-Regulated Transcription Coactivator 3
复制标题
DOI：
10.1523/jneurosci.1345-14.2015
复制
发表时间：
2015-09-02
影响因子：
5.3
通讯作者：
van den Burg, Erwin H.
中科院分区：
文献类型：
--
作者：
Jurek, Benjamin;Slattery, David A.;van den Burg, Erwin H.
脑中神经内分泌应激反应的主要调节因子是促肾上腺皮质激素释放因子（CRF），其转录由CREB及其辅因子CRTC 2/3（TORC 2/3）控制。磷酸化的CRTC被隔离在细胞质中，但在应激刺激后迅速去磷酸化并易位到细胞核中。由于应激反应被催产素（OT）减弱，我们测试了OT是否干扰CRTC易位，从而干扰Crf表达。OT（1 nmol，i.c.v.）延迟应激诱导的雄性大鼠和小鼠室旁核中核CRTC 3和Crf hnRNA水平的增加，但在没有应激源的情况下不影响任何参数。Crf hnRNA水平在随后时间点的增加与核CRTC 2/3水平升高平行。在大鼠原代下丘脑神经元、杏仁核（Ar-5）、下丘脑（H32）和人神经母细胞瘤（Be（2）M17）细胞系中发现Thr（4）Gly（7）-OT（TGOT）对CRTC 3易位和Crf表达的直接作用。在Be（2）M17细胞中使用siRNA敲低CRTC 3而不是CRCT 2阻止了TGOT对Crf hnRNA水平的影响。染色质免疫沉淀表明，TGOT减少CRTC 3，但不是CRTC 2，结合到Crf启动子后10分钟的毛喉素刺激。总之，结果表明，OT调节CRTC 3易位，CRTC 3的Crf启动子的结合，并最终，Crf基因的转录。
The major regulator of the neuroendocrine stress response in the brain is corticotropin releasing factor (CRF), whose transcription is controlled by CREB and its cofactors CRTC2/3 (TORC2/3). Phosphorylated CRTCs are sequestered in the cytoplasm, but rapidly dephosphorylated and translocated into the nucleus following a stressful stimulus. As the stress response is attenuated by oxytocin (OT), we tested whether OT interferes with CRTC translocation and, thereby, Crf expression. OT(1 nmol, i.c.v.) delayed the stress-induced increase of nuclear CRTC3 and Crf hnRNA levels in the paraventricular nucleus of male rats and mice, but did not affect either parameter in the absence of the stressor. The increase in Crf hnRNA levels at later time points was parallel to elevated nuclear CRTC2/3 levels. A direct effect of Thr(4) Gly(7)-OT (TGOT) on CRTC3 translocation and Crf expression was found in rat primary hypothalamic neurons, amygdaloid (Ar-5), hypothalamic (H32), and human neuroblastoma (Be(2)M17) cell lines. CRTC3, but not CRCT2, knockdown using siRNA in Be(2)M17 cells prevented the effect of TGOT on Crf hnRNA levels. Chromatin-immunoprecipitation demonstrated that TGOT reduced CRTC3, but not CRTC2, binding to the Crf promoter after 10 min of forskolin stimulation. Together, the results indicate that OT modulates CRTC3 translocation, the binding of CRTC3 to the Crf promoter and, ultimately, transcription of the Crf gene.