Department of Molecular Virology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Genes Cells. 2012 Aug;17(8):660-72. doi: 10.1111/j.1365-2443.2012.01617.x. Epub 2012 Jun 15.
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.
区分致癌生长信号和正常生长信号对于肿瘤抑制至关重要。转录因子 E2F 是 pRB 的主要靶标，通过激活促进生长的基因在细胞增殖中发挥核心作用。E2F 还通过激活促凋亡基因等生长抑制基因在肿瘤抑制中发挥重要作用。这些基因的调控机制尚不清楚，尤其是在应对正常和致癌生长信号时。E2F 通过 pRB 的磷酸化被生长刺激生理性激活。相比之下，在 pRB 功能障碍（一种主要的致癌变化）时，E2F 会失控激活，产生失调的 E2F 活性。我们在这里表明，肿瘤抑制因子 TAp73 基因可以独立于 p53 诱导细胞凋亡，它响应失调的 E2F 活性，但对人正常成纤维细胞中生长刺激诱导的生理性 E2F 活性没有反应。我们在 TAp73 启动子中鉴定了 E2F 反应元件（ERE73s），它们可以特异性感知失调的 E2F 活性。此外，RB1 缺陷型癌细胞系中存在失调的 E2F 活性，该活性激活了 ERE73s 和 TAp73 基因，而 pRB 的重新引入则抑制了它们的活性。这些结果强调了失调的 E2F 在激活 TAp73 基因中的重要作用，该基因是主要内在肿瘤抑制途径的组成部分。
