Distinct E2F-mediated transcriptional program regulates p14ARF gene expression
Distinct E2F-mediated transcriptional program regulates p14ARF gene expression
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DOI：
10.1038/sj.emboj.7600836
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发表时间：
2005-11-02
期刊：
影响因子：
11.4
通讯作者：
Ohtani, K
中科院分区：
文献类型：
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作者：
Komori, H;Enomoto, M;Ohtani, K
肿瘤抑制基因p14（ARF）是由异位表达的E2 F诱导的，E2 F是细胞周期的正调控因子。该基因在正常生长的细胞中表达水平较低，而在各种肿瘤中表达水平较高。在正常生长的细胞和肿瘤细胞中，E2 F如何调控p14（ARF）基因的表达尚不清楚。在这里，我们表明，调节p14（ARF）基因的E2 F是不同于经典的E2 F的目标。它是由E2 F通过一个新的E2 F反应元件，从典型的E2 F网站不同直接介导的。该元件响应E2 F活性导致异位E2 F1的表达，腺病毒E1 a或shRNA的pRb的失活，但不磷酸化的pRb的血清刺激或异位细胞周期蛋白D1/细胞周期蛋白依赖性激酶-4在正常人成纤维细胞的表达。该元素在各种pRb缺陷的肿瘤细胞中具有活性，但在正常生长的细胞中不具有活性。这些结果表明，不同的调节构成了p14（ARF）作为肿瘤抑制因子的功能的基础，区分由pRb功能缺陷引起的异常生长信号与正常生长信号。
The tumor suppressor p14(ARF) gene is induced by ectopically expressed E2F, a positive regulator of the cell cycle. The gene is expressed at low levels in normally growing cells in contrast to high levels in varieties of tumors. How p14(ARF) gene is regulated by E2F in normally growing cells and tumor cells remains obscure. Here we show that regulation of p14(ARF) gene by E2F is distinct from that of classical E2F targets. It is directly mediated by E2F through a novel E2F-responsive element that varies from the typical E2F site. The element responds to E2F activity resulting from ectopic E2F1 expression, inactivation of pRb by adenovirus E1a or shRNA, but not to phosphorylation of pRb by serum stimulation or ectopic cyclin D1/cyclin-dependent kinase-4 expression in normal human fibroblasts. The element has activity in various tumor cells with defective pRb, but not in normally growing cells. These results indicate that the distinct regulation constitutes the basis of p14(ARF) function as a tumor suppressor, discriminating abnormal growth signals caused by defects in pRb function from normal growth signals.