Novel Mechanisms for IGF-I Regulation by Glucagon in Carp Hepatocytes: Up-Regulation of HNF1α and CREB Expression via Signaling Crosstalk for IGF-I Gene Transcription
Novel Mechanisms for IGF-I Regulation by Glucagon in Carp Hepatocytes: Up-Regulation of HNF1α and CREB Expression via Signaling Crosstalk for IGF-I Gene Transcription
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DOI：
10.3389/fendo.2019.00605
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发表时间：
2019-09-03
影响因子：
5.2
通讯作者：
Wong, Anderson O. L.
中科院分区：
文献类型：
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作者：
Bai, Jin;Jiang, Xue;Wong, Anderson O. L.
胰高血糖素是维持葡萄糖稳态的关键激素，通过调节IGF-I的表达与生长激素轴发生功能性交叉。然而，其对IGF-I调节的影响在不同的研究中差异很大，所涉及的机制在很大程度上是未知的。以草鱼为模型，研究了胰高血糖素对鲤类动物IGF-I调控的信号转导和转录机制。作为第一步，鲤鱼HNF 1 α，肝脏富集的转录因子，被克隆，并证实是一个单拷贝的基因在肝脏中表达。在草鱼肝细胞中，胰高血糖素处理可升高IGF-I、HNF 1 α和CREB mRNA水平，诱导CREB磷酸化，并上调HNF 1 α和CREB蛋白表达。对IGF-I、HNF 1 α和CREB基因表达的影响由cAMP/PKA和PLC/IP 3/PKC途径介导，并与MAPK和PI 3 K/Akt级联反应发生差异偶联。在此过程中，HNF 1 α和CREB之间的蛋白质：蛋白质相互作用以及RNA Pol-II向IGF-I启动子的募集也随着IGF-I初级转录水平的升高而发生。在检测草鱼IGF-I启动子在α T3细胞中表达的活性的平行研究中，胰高血糖素诱导的IGF-I启动子激活中也证实了类似的受体后信号传导途径，并且胰高血糖素的反式激活作用是由位于IGF-I启动子近端区域的HNF 1 α和CREB的结合位点介导的。我们的研究结果，作为一个整体，揭示了一个以前未描述的机制，胰高血糖素诱导的IGF-I基因表达，通过增加HNF 1 α和CREB的生产，通过功能串扰后受体信号。很可能，通过两种转录因子之间的蛋白质：蛋白质相互作用和随后通过IGF-I启动子中各自的顺式作用元件的反式激活，IGF-I基因转录可以在肝脏水平上由胰高血糖素启动。
Glucagon, a key hormone for glucose homeostasis, can exert functional crosstalk with somatotropic axis via modification of IGF-I expression. However, its effect on IGF-I regulation is highly variable in different studies and the mechanisms involved are largely unknown. Using grass carp as a model, the signal transduction and transcriptional mechanisms for IGF-I regulation by glucagon were examined in Cyprinid species. As a first step, the carp HNF1 alpha, a liver-enriched transcription factor, was cloned and confirmed to be a single-copy gene expressed in the liver. In grass carp hepatocytes, glucagon treatment could elevate IGF-I, HNF1 alpha, and CREB mRNA levels, induce CREB phosphorylation, and up-regulate HNF1 alpha and CREB protein expression. The effects on IGF-I, HNF1 alpha, and CREB gene expression were mediated by cAMP/PKA and PLC/IP3/PKC pathways with differential coupling with the MAPK and PI3K/Akt cascades. During the process, protein:protein interaction between HNF1 alpha and CREB and recruitment of RNA Pol-II to IGF-I promoter also occurred with a rise in IGF-I primary transcript level. In parallel study to examine grass carp IGF-I promoter activity expressed in alpha T3 cells, similar pathways for post-receptor signaling were also confirmed in glucagon-induced IGF-I promoter activation and the trans-activating effect by glucagon was mediated by the binding sites for HNF1 alpha and CREB located in the proximal region of IGF-I promoter. Our findings, as a whole, shed light on a previously undescribed mechanism for glucagon-induced IGF-I gene expression by increasing HNF1 alpha and CREB production via functional crosstalk of post-receptor signaling. Probably, by protein:protein interaction between the two transcription factors and subsequent transactivation via their respective cis-acting elements in the IGF-I promoter, IGF-I gene transcription can be initiated by glucagon at the hepatic level.