Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China; School of Rehabilitation Sciences, Seirei Christopher University, Hamamatsu, 433-8558, Japan.
Cancer Lett. 2015 Jan 28;356(2 Pt B):910-7. doi: 10.1016/j.canlet.2014.10.044. Epub 2014 Nov 7.
One of the most important tumor suppression functions of p53 is its ability to induce apoptosis. iASPP is an inhibitory member of the ASPP protein family. It can specifically inhibit the normal function of p53 as a suppressor. The mechanism of iASPP suppressing the cell apoptotosis is through inhibiting the transactivation function of p53 on the promoters of proapoptotic genes by binding with p53. Therefore, relieving the combination of iASPP with p53 and leaving p53 free may be a useful strategy to activate p53 function. We therefore use A34, a small peptide derived from p53 linker region, to investigate the possibility of resuming the apoptosis activity of p53 by sequestering iASPP with p53 and derepressing p53. The results show that A34 can competitively combine with iASPP and therefore release p53 from iASPP; A34 can enhance the transcriptional activity of p53 on the promoters of Bax and PUMA; A34 can increase cell apoptosis and slow tumor growth in vitro and vivo. This study will open the way for using small molecule peptides that directly disturb the interaction of p53 with iASPP, thereby resume function of p53 as a suppressor.
p53 的最重要的肿瘤抑制功能之一是其诱导细胞凋亡的能力。iASPP 是 ASPP 蛋白家族的抑制成员。它可以特异性地抑制 p53 作为抑癌基因的正常功能。iASPP 抑制细胞凋亡的机制是通过与 p53 结合，抑制 p53 对促凋亡基因启动子的转录激活功能。因此，解除 iASPP 与 p53 的结合并使 p53 游离可能是激活 p53 功能的一种有效策略。因此，我们使用 A34，一种来源于 p53 连接区的小肽，来研究通过与 p53 结合来隔离 iASPP 并使 p53 去抑制的可能性，从而恢复 p53 的凋亡活性。结果表明，A34 可以与 iASPP 竞争结合，从而使 p53 从 iASPP 上释放；A34 可以增强 p53 在 Bax 和 PUMA 启动子上的转录活性；A34 可以增加细胞凋亡并减缓体外和体内肿瘤的生长。这项研究将为使用小分子肽直接干扰 p53 与 iASPP 的相互作用，从而恢复 p53 作为抑癌基因的功能开辟道路。
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