Multiple chromatin-bound protein kinases assemble factors that regulate insulin gene transcription
Multiple chromatin-bound protein kinases assemble factors that regulate insulin gene transcription
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DOI：
10.1073/pnas.0912596106
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发表时间：
2009-12-29
影响因子：
11.1
通讯作者：
Cobb, Melanie H.
中科院分区：
文献类型：
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作者：
Lawrence, Michael C.;Shao, Chunli;Cobb, Melanie H.
在糖尿病发作期间，胰腺β细胞变得无法产生足够的胰岛素以将血糖维持在正常范围内。促炎细胞因子与β细胞功能受损有关。为了进一步了解降低胰岛素基因转录的分子事件，我们研究了高血糖单独和与促炎细胞因子白细胞介素-1 β（IL-1 β）一起对调节胰岛素基因转录的信号转导途径的影响。在空腹葡萄糖中暴露于IL-1 β激活与胰岛素基因启动子相关的多种蛋白激酶，并瞬时增加β细胞中胰岛素基因转录。相反，暴露于高血糖条件下的细胞对IL-1 β的抑制作用敏感。在这些条件下，IL-1 β导致相同的蛋白激酶，但不同的组合与胰岛素基因启动子的转录因子的协会，并开始减少转录在2小时内，刺激因子丢失，RNA聚合酶II丢失，抑制因子结合到启动子在激酶依赖性的方式。
During the onset of diabetes, pancreatic beta cells become unable to produce sufficient insulin to maintain blood glucose within the normal range. Proinflammatory cytokines have been implicated in impaired beta cell function. To understand more about the molecular events that reduce insulin gene transcription, we examined the effects of hyperglycemia alone and together with the proinflammatory cytokine interleukin-1 beta(IL-1 beta) on signal transduction pathways that regulate insulin gene transcription. Exposure to IL-1 beta in fasting glucose activated multiple protein kinases that associate with the insulin gene promoter and transiently increased insulin gene transcription in beta cells. In contrast, cells exposed to hyperglycemic conditions were sensitized to the inhibitory actions of IL-1 beta. Under these conditions, IL-1 beta caused the association of the same protein kinases, but a different combination of transcription factors with the insulin gene promoter and began to reduce transcription within 2 h; stimulatory factors were lost, RNA polymerase II was lost, and inhibitory factors were bound to the promoter in a kinase-dependent manner.