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首页> 外文期刊>American Journal of Physiology >Induced ATF-2 represses CDK4 transcription through dimerization with JunD inhibiting intestinal epithelial cell growth after polyamine depletion.
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Induced ATF-2 represses CDK4 transcription through dimerization with JunD inhibiting intestinal epithelial cell growth after polyamine depletion.

机译：诱导的ATF-2通过与JunD抑制聚胺消耗后肠上皮细胞生长的二聚作用来抑制CDK4转录。

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摘要

Intestinal epithelium is a rapidly self-renewing tissue in the body, and its homeostasis is tightly regulated by numerous factors including polyamines. Decreased levels of cellular polyamines increase activating transcription factor (ATF)-2, but the exact role and mechanism of induced ATF-2 in the regulation of intestinal epithelial cell (IEC) growth remain elusive. Cyclin-dependent kinase (CDK) 4 is necessary for the G1-to-S phase transition during the cell cycle, and its expression is predominantly controlled at the transcription level. Here, we reported that induced ATF-2 following polyamine depletion repressed CDK4 gene transcription in IECs by increasing formation of the ATF-2/JunD heterodimers. ATF-2 formed complexes with JunD as measured by immunoprecipitation using the ATF-2 and JunD antibodies and by glutathione S-transferase (GST) pull-down assays using GST-ATF-2 fusion proteins. Studies using various mutants of GST-ATF-2 revealed that formation of the ATF-2/JunD dimers depended on the COOH-terminal basic region-leucine zipper domain of ATF-2. Polyamine depletion increased ATF-2/JunD complex and inhibited CDK4 transcription as indicated by a decrease in the levels of CDK4-promoter activity and its mRNA. ATF-2 silencing not only prevented inhibition of CDK4 transcription in polyamine-deficient cells but also abolished repression of CDK4 expression induced by ectopic JunD overexpression. ATF-2 silencing also promoted IEC growth in polyamine-depleted cells. These results indicate that induced ATF-2/JunD association following polyamine depletion represses CDK4 transcription, thus contributing to the inhibition of IEC growth.
机译：肠上皮是人体中快速自我更新的组织，其体内平衡受多种因素（包括多胺）的严格调节。细胞多胺水平降低会增加激活转录因子（ATF）-2，但诱导的ATF-2在调控肠上皮细胞（IEC）生长中的确切作用和机制仍然难以捉摸。细胞周期中从G1到S的相变必须依赖细胞周期蛋白依赖性激酶（CDK）4，其表达主要在转录水平上控制。在这里，我们报道了多胺耗竭后诱导的ATF-2通过增加ATF-2 / JunD异二聚体的形成抑制了IECs中CDK4基因的转录。通过使用ATF-2和JunD抗体进行免疫沉淀，以及使用GST-ATF-2融合蛋白进行的谷胱甘肽S-转移酶（GST）下拉测定，ATF-2与JunD形成了复合物。使用各种GST-ATF-2突变体的研究表明，ATF-2 / JunD二聚体的形成取决于ATF-2的COOH末端碱性区域-亮氨酸拉链结构域。多胺耗竭增加了ATF-2 / JunD复合物并抑制了CDK4转录，如CDK4启动子活性及其mRNA水平的降低所表明。 ATF-2沉默不仅阻止了多胺缺陷细胞中CDK4转录的抑制，而且消除了异位JunD过表达诱导的CDK4表达的抑制。 ATF-2沉默还促进了贫多胺细胞中IEC的生长。这些结果表明，多胺耗竭后诱导的ATF-2 / JunD缔合抑制CDK4转录，从而有助于抑制IEC的生长。

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