Pathophysiological mechanism through the regulation of the transcriptional factor, c-fos, gene expression.

病理生理机制通过转录因子c-fos、基因表达的调节。

• 批准号: 11670437
• 负责人: IGARASHI Tetsuya
• 金额: $ 1.86万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670437/
• 关键词: stress stimuli; heat shock; c-fos; prostaglandin; endocrine disruptor; estrogen; 転写調節

1) Elevation of c-fos gene and AP-1 activity induced by stressesAlthough it has been widely accepted that the c-fos gene, which is responsive to various stresses, does not harbor the heat shock element (HSE) in its upstream region, we found the consensus-sequence for the HSE in the human, rat and mouse genes (BBRC 254:566, 1999). Since rostaglandin A1 (PGA1) increases heat shock element (HSE)-mediated transcription, thereby enhancing expression of HSE-bearing genes, including heat shock proteins, we hypothesized that PGA1 might increase c-fos expression through the HSE. Following investigation has revealed that c-fos expression at least partly by increasing the binding between heat shock factor-1 and the HSE, and that PGA1 enhances activity of activating protein-1 (AP-1). Interestingly, so far as PGA1 is present in the medium, AP-1-mediated transcription enhanced by PGA1 cannot be detected by the standard luciferase reporter gene assay. Instead, it can be detected by either checking lu … More ciferase mRNA levels in the presence of PGA1 or measuring luciferase activities just after removal of PGA1. These results shows that protein products of some stress-responsive genes can increase, not during the stressful condition, but immediately after recovery from stress(MCE 164:77, 2000).2) Detection of environmental hormone-like substancesIn the process of the studies on HSE, we have been interested in estrogenic activity because it can enhance expression of c-fos gene as well as heat shock proteins. Since we often experienced troubles with the assay for luciferase in control dishes, we got suspicious of the existence of hormone-like substances with estrogenic activity released from the culture dishes. Our experiments reveals that many types of polystyrene dishes release estrogenic impurities, a property that should be taken into account when carrying out research using estrogen-responsive cells or studying the cellular effects of this hormone and its analogs (Nature Biotechnology 19:812, 2001). Less

1)应激诱导的c-fos基因和AP-1活性的升高尽管人们普遍认为对各种应激反应敏感的c-fos基因在其上游区域不含有热休克元件（HSE），但我们在人、大鼠和小鼠基因中发现了HSE的共有序列（BBRC 254：566，1999）。由于前列腺素A1（PGA 1）增加热休克元件（HSE）介导的转录，从而提高表达的HSE轴承基因，包括热休克蛋白，我们假设，PGA 1可能通过HSE增加c-fos的表达。进一步研究表明，c-fos的表达至少部分是通过增加热休克因子-1与HSE的结合而实现的，而PGA 1则增强了激活蛋白-1（AP-1）的活性。有趣的是，只要培养基中存在PGA 1，标准荧光素酶报告基因测定法就不能检测到PGA 1增强的AP-1介导的转录。相反，可以通过检查lu ...更多信息 在PGA 1存在下的ciferase mRNA水平或在除去PGA 1后立即测量荧光素酶活性。这些结果表明，一些应激反应基因的蛋白产物可以增加，而不是在应激条件下，但从应激中恢复后立即（MCE 164：77，2000）。2）环境激素样物质的检测在HSE的研究过程中，我们一直感兴趣的雌激素活性，因为它可以增强c-fos基因和热休克蛋白的表达。由于我们经常在对照皿中的荧光素酶测定中遇到麻烦，我们怀疑存在从培养皿中释放的具有雌激素活性的类雌激素物质。我们的实验表明，许多类型的聚苯乙烯皿释放雌激素杂质，当使用雌激素响应细胞进行研究或研究这种激素及其类似物的细胞效应时，应该考虑到这一特性（Nature Biotechnology 19：812，2001）。少

项目成果

Ishikawa T,Igarashi T,Hata K,Fujita T: "Prostaglandin E2 enhances estrogen receptor a-mediated transcription possibly not via activation of prostanoid receptors."82nd annual meeting of The Endocrine Society. (2000)

Ishikawa T、Igarashi T、Hata K、Fujita T：“前列腺素 E2 可能不通过前列腺素受体的激活来增强雌激素受体 a 介导的转录。”内分泌学会第 82 届年会。

Nishimori S, Tanaka Y, Chiba T, Igarashi T, et al.: "Smad-mediated transcription is required for TGF-beta1-induced p57Kip2 Proteolysis in Osteoblastic Cells"The Journal of Biological Chemistry. 276(14). 10700-10705 (2001)

Nishimori S、Tanaka Y、Chiba T、Igarashi T 等人：“成骨细胞中 TGF-β1 诱导的 p57Kip2 蛋白水解需要 Smad 介导的转录”《生物化学杂志》。

Toshio Ishikawa, Nobuo Sekine, Keishi Hata, Tetsuya Igarashi, Toshiro Fujita: "Prostaglandin A1 enhances c-fos expression and activating protein-1 activity."Molecular and Cellular Endocrinology. 164. 77-85 (2000)

Toshio Ishikawa、Nobuo Sekine、Keishi Hata、Tetsuya Igarashi、Toshiro Fujita：“前列腺素 A1 增强 c-fos 表达并激活 Protein-1 活性。”分子和细胞内分泌学。

Igarashi T,Ogata E,Maruyama K,Fukuda T,Azuma J: "Effect of Calcimimetic Agent,KRN568,on Gastrin Secretion in Healthy Subjects."Endocrine J.. 47. 517-523 (2000)

Igarashi T、Ogata E、Maruyama K、Fukuda T、Azuma J：“拟钙剂 KRN568 对健康受试者胃泌素分泌的影响。”内分泌 J.. 47. 517-523 (2000)

Ishikawa T, Sekine N, Igarashi T, et al.: "Prostaglandin A1 enhances c-fos expression and activating protein-1 activity"Molecular and Cellular Endocrinology. 164. 77-85 (2000)

Ishikawa T、Sekine N、Igarashi T 等人：“前列腺素 A1 增强 c-fos 表达并激活 Protein-1 活性”分子和细胞内分泌学。