E2F-like elements in p27Kip1 promoter specifically sense deregulated E2F activity
E2F-like elements in p27Kip1 promoter specifically sense deregulated E2F activity
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DOI：
10.1111/j.1365-2443.2008.01248.x
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发表时间：
2009-01-01
期刊：
影响因子：
2.1
通讯作者：
Ohtani, Kiyoshi
中科院分区：
文献类型：
--
作者：
Ozono, Eiko;Komori, Hideyuki;Ohtani, Kiyoshi
转录因子E2F是RB肿瘤抑制途径的主要靶点，不仅在细胞增殖中而且在肿瘤抑制中起着至关重要的作用。细胞周期蛋白依赖性激酶抑制剂p27（Kip1）基因是E2F的上游负调节因子，其由异位表达的E2F1诱导，而不是由生理上激活内源性E2F的正常生长刺激诱导。这表明该基因可以区分失调和生理E2F活性。为了解决这个问题，我们研究了E2F对p27（Kip1）基因的调控。在这里，我们表明，p27（Kip1）启动子通过类似于典型的E2F位点的元件特异性地感知失调的E2F活性。这E2F样元素激活的失调E2F活性诱导的pRb的强制失活，但不是由生理E2F活性诱导的血清刺激，相反，典型的E2F网站激活的E2F活性。内源性p27（Kip1）基因以与E2F样元件相同的方式对失调和生理性E2F活性作出反应。此外，E2F样元件结合异位表达的E2F1，但在体内不结合生理活化的E2F1或E2F4。这些结果表明，p27（Kip1）基因特异性地通过E2F样元件感应失调的E2F活性，以抑制不适当的细胞周期进程，以响应pRb功能的丧失。
The transcription factor E2F, the main target of the RB tumor suppressor pathway, plays crucial roles not only in cell proliferation but also in tumor suppression. The cyclin-dependent kinase inhibitor p27(Kip1) gene, an upstream negative regulator of E2F, is induced by ectopically expressed E2F1 but not by normal growth stimulation that physiologically activates endogenous E2F. This suggests that the gene can discriminate between deregulated and physiological E2F activity. To address this issue, we examined regulation of the p27(Kip1) gene by E2F. Here we show that p27(Kip1) promoter specifically senses deregulated E2F activity through elements similar to typical E2F sites. This E2F-like elements were activated by deregulated E2F activity induced by forced inactivation of pRb but not by physiological E2F activity induced by serum stimulation, contrary to typical E2F sites activated by both E2F activity. The endogenous p27(Kip1) gene responded to deregulated and physiological E2F activity in the same manner to the E2F-like elements. Moreover, the E2F-like elements bound ectopically expressed E2F1 but not physiologically activated E2F1 or E2F4 in vivo. These results suggest that the p27(Kip1) gene specifically senses deregulated E2F activity through the E2F-like elements to suppress inappropriate cell cycle progression in response to loss of pRb function.