The short isoform of the ubiquitin ligase NEDD4L is a CREB target gene in hepatocytes.
The short isoform of the ubiquitin ligase NEDD4L is a CREB target gene in hepatocytes.
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DOI：
10.1371/journal.pone.0078522
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Berdeaux R
中科院分区：
文献类型：
--
作者：
Fu J;Akhmedov D;Berdeaux R
在禁食和喂养周期中，肝脏功能受到转录和翻译后事件的调节。在不同的营养条件下，调节蛋白质降解已成为控制特定肝脏蛋白质丰度的关键机制。由于通过cAMP和PKA的胰高血糖素信号通路是禁食期间葡萄糖输出的核心，我们假设该信号通路也可能调节禁食状态下的泛素连接酶。本研究表明，禁食刺激促进原代小鼠肝细胞中E3泛素连接酶Nedd4l短异构体的表达。禁食期间，NEDD4L -short mRNA和NEDD4L（短异构体）蛋白在胰高血糖素处理的原代小鼠肝细胞和肝组织中积累。我们在交替的Nedd4l-short启动子中发现了一个功能性cAMP反应元件；该元件的突变会减弱camp诱导的Nedd4l报告结构的表达。CREB占据该元件附近的内源性nedd41位点。CREB及其共激活因子CRTC2均可被禁食刺激激活，促进胰高血糖素刺激的Nedd4l-short在原代肝细胞中的表达。原代肝细胞中sirna介导的Nedd4l缺失不影响糖异生基因表达、葡萄糖输出或糖原合成。我们的发现揭示了Nedd4l在肝细胞中转录调控的新机制。
During cycles of fasting and feeding, liver function is regulated by both transcriptional and post-translational events. Regulated protein degradation has recently emerged as a key mechanism to control abundance of specific hepatic proteins under different nutritional conditions. As glucagon signaling through cAMP and PKA is central to glucose output during fasting, we hypothesized that this signaling pathway may also regulate ubiquitin ligases in the fasted state. Here we show that fasting stimuli promote expression of the short isoform of the E3 ubiquitin ligase Nedd4l in primary mouse hepatocytes. Nedd4l-short mRNA and NEDD4L (short isoform) protein accumulate in glucagon-treated primary mouse hepatocytes and in liver tissues during fasting. We identified a functional cAMP response element in the alternate Nedd4l-short promoter; mutation of this element blunts cAMP-induced expression of a Nedd4l reporter construct. CREB occupies the endogenous Nedd4l locus near this element. CREB and its co-activator CRTC2, both activated by fasting stimuli, contribute to glucagon-stimulated Nedd4l-short expression in primary hepatocytes. siRNA-mediated Nedd4l depletion in primary hepatocytes did not affect gluconeogenic gene expression, glucose output or glycogen synthesis. Our findings reveal a new mechanism of Nedd4l transcriptional regulation in liver cells.
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影响因子：
64.8
作者：
Liu, Yi;Dentin, Renaud;Chen, Danica;Hedrick, Susan;Ravnskjaer, Kim;Schenk, Simon;Milne, Jill;Meyers, David J.;Cole, Phil;Yates, John, III;Olefsky, Jerrold;Guarente, Leonard;Montminy, Marc
通讯作者：
Montminy, Marc
影响因子：
29
作者：
Le Lay J;Tuteja G;White P;Dhir R;Ahima R;Kaestner KH
通讯作者：
Kaestner KH
DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
16.6
作者：
Boase, Natasha A.;Rychkov, Grigori Y.;Townley, Scott L.;Dinudom, Anuwat;Candi, Eleanora;Voss, Anne K.;Tsoutsman, Tatiana;Semsarian, Chris;Melino, Gerry;Koentgen, Frank;Cook, David I.;Kumar, Sharad
通讯作者：
Kumar, Sharad
影响因子：
64.8
作者：
Herzig, S;Hedrick, S;Montminy, M
通讯作者：
Montminy, M