Tumor suppressor TAp73 gene specifically responds to deregulated E2F activity in human normal fibroblasts
Tumor suppressor TAp73 gene specifically responds to deregulated E2F activity in human normal fibroblasts
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DOI：
10.1111/j.1365-2443.2012.01617.x
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发表时间：
2012-08-01
期刊：
影响因子：
2.1
通讯作者：
Ohtani, Kiyoshi
中科院分区：
文献类型：
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作者：
Ozono, Eiko;Komori, Hideyuki;Ohtani, Kiyoshi
区分致癌生长信号与正常生长信号对于肿瘤抑制至关重要。转录因子E2F是pRB的主要靶点，通过激活促生长基因在细胞增殖中发挥核心作用。E2F还通过激活生长抑制基因如促凋亡基因在肿瘤抑制中起重要作用。后者基因的调控机制尚不清楚，特别是对正常和致癌生长信号的反应。E2F通过pRB的磷酸化被生长刺激生理激活。相反，在pRB功能障碍时，一种主要的致癌变化，E2F被pRB激活而不受控制，产生失调的E2F活性。我们在这里表明，肿瘤抑制基因TAp73，它可以诱导凋亡的p53独立，响应于失调E2F活性，但不生理E2F活性诱导的生长刺激在人类正常成纤维细胞。我们在TAp 73启动子中鉴定了E2 F响应元件（ERE 73 s），该元件可以特异性检测失调的E2 F活性。此外，RB 1缺陷癌细胞系具有失调的E2 F活性，该活性激活ERE 73 s和TAp 73基因，而这些基因通过重新引入pRB而被抑制。这些结果强调了E2F在TAp73基因激活中的重要作用，TAp73基因是主要的内源性肿瘤抑制途径的一个组成部分。
Discrimination of oncogenic growth signals from normal growth signals is crucial for tumor suppression. The transcription factor E2F, the main target of pRB, plays central role in cell proliferation by activating growth-promoting genes. E2F also plays an important role in tumor suppression by activating growth-suppressive genes such as pro-apoptotic genes. The regulatory mechanism of the latter genes is not known in detail, especially in response to normal and oncogenic growth signals. E2F is physiologically activated by growth stimulation through phosphorylation of pRB. In contrast, upon dysfunction of pRB, a major oncogenic change, E2F is activated out of control by pRB, generating deregulated E2F activity. We show here that the tumor suppressor TAp73 gene, which can induce apoptosis independently of p53, responds to deregulated E2F activity, but not to physiological E2F activity induced by growth stimulation in human normal fibroblasts. We identified E2F-responsive elements (ERE73s) in TAp73 promoter that can specifically sense deregulated E2F activity. Moreover, RB1-deficient cancer cell lines harbored deregulated E2F activity that activated ERE73s and the TAp73 gene, which were suppressed by re-introduction of pRB. These results underscore the important role of deregulated E2F in activation of the TAp73 gene, a component of major intrinsic tumor suppressor pathways.