The antiestrogen tamoxifen induces c-fos and jun-B, but not c-jun or jun-D, protooncogenes in the rat uterus.
The antiestrogen tamoxifen induces c-fos and jun-B, but not c-jun or jun-D, protooncogenes in the rat uterus.
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DOI：
10.1210/endo.133.1.8319588
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发表时间：
1993-07
期刊：
影响因子：
4.8
通讯作者：
K. Nephew;T. C. Polek;K. Akcali;Sohaib A. Khan
中科院分区：
文献类型：
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作者：
K. Nephew;T. C. Polek;K. Akcali;Sohaib A. Khan
他莫昔芬是治疗乳腺癌的主要药物。虽然被归类为抗雌激素，他莫昔芬在大鼠子宫中显示部分雌激素激动剂活性。他莫昔芬子宫增重作用的分子机制尚不清楚。本研究的目的是探讨三苯氧胺对大鼠子宫内c-fos、c-jun、jun-B和jun-D原癌基因激活的影响。这些立即早期反应基因是转录调节因子，可以调节含有AP-1识别位点的基因的表达。总子宫RNA的北方印迹分析显示，治疗的成年，卵巢切除大鼠与他莫昔芬升高水平的c-fos mRNA的2.4-，5.3-和6.2-倍，在未经处理的大鼠分别在6，12和24小时后，他莫昔芬注射。注射后48 h，他莫昔芬对c-fos的诱导作用仍然明显。他莫昔芬对jun基因家族表达的影响也进行了研究。他莫昔芬显着诱导子宫表达jun-B mRNA的约10倍的表达在未处理的大鼠给药后24小时。到48小时，jun-B转录水平下降到对照值的2.3倍。与此相反，只有轻微的诱导c-jun和jun-D的表达（1.3和1.6倍，分别）12小时后，他莫昔芬治疗观察。他莫昔芬诱导的这些基因表达的动力学模式与其他刺激的报道有显著不同，雌激素.这是第一次报告，以检查他莫昔芬对大鼠子宫原癌基因表达的影响。我们的研究结果表明，立即早期反应基因的激活可能在他莫昔芬的子宫增重作用中发挥作用。然而，基于诱导的动力学，我们认为他莫昔芬在原癌基因的转录激活方面比其他子宫激动剂，雌激素.缺乏同步表达的jun基因可能表明，不同的控制机制存在于这个原癌基因家族的成员。
Tamoxifen is the leading therapeutic agent in the management of breast cancer. Although classified as an antiestrogen, tamoxifen displays partial estrogen agonist activity in the rat uterus. The molecular mechanism of the uterotrophic action of tamoxifen is unclear. The purpose of the present study was to investigate the effect of tamoxifen on activation of the c-fos, c-jun, jun-B and jun-D protooncogenes in rat uteri in vivo. These immediate early response genes are transcription regulatory factors that can regulate the expression of genes containing an AP-1 recognition site. Northern blotting analysis of total uterine RNA revealed that treatment of adult, ovariectomized rats with tamoxifen elevated levels of c-fos mRNA 2.4-, 5.3- and 6.2-fold over expression in untreated rats by 6, 12 and 24 h post-tamoxifen injection, respectively. Tamoxifen induction of c-fos was still apparent by 48 h post injection. The effect of tamoxifen on expression of the jun gene family was also examined. Tamoxifen markedly induced uterine expression of jun-B mRNA by approximately 10-fold over expression in untreated rats by 24 h after administration. By 48 h, levels of jun-B transcripts had declined to 2.3 fold over control values. In contrast, only slight induction of c-jun and jun-D expression (1.3- and 1.6-fold, respectively) by 12 h after tamoxifen treatment was observed. The kinetic pattern of tamoxifen-induced expression of these genes was strikingly different from what has been reported for other stimuli, e.g., estrogen. This is the first report to examine the effects of tamoxifen on protooncogene expression in the rat uterus. Our results indicate that the activation of immediate early response genes may play a role in the uterotrophic actions of tamoxifen. However, based on the kinetics of induction, we suggest that tamoxifen is much less effective at transcriptional activation of protooncogenes than other uterine agonists, e.g., estrogen. The lack of synchronous expression of the jun genes may indicate that distinct control mechanisms exist among members of this protooncogene family.