Functional profiling of p53-binding sites in Hdm2 and Hdmx using a genetic selection system.
Functional profiling of p53-binding sites in Hdm2 and Hdmx using a genetic selection system.
复制标题
使用遗传选择系统对 Hdm2 和 Hdmx 中的 p53 结合位点进行功能分析。
DOI：
10.1016/j.bmc.2010.06.053
复制
发表时间：
2010
影响因子：
3.5
通讯作者：
Savinov,SergeyN
中科院分区：
文献类型：
--
作者：
Datta,Shreya;Bucks,MeganE;Koley,Dipankar;Lim,PeiXin;Savinov,SergeyN
结构上同源的癌蛋白Hdm 2和Hdmx的上调与其共同调节靶点肿瘤抑制因子p53蛋白的耗竭或失活有关，从而导致癌症的进展。因此，通过这些负调节剂使p53功能被抑制或休眠，p53功能的恢复为在保留野生型p53的癌症中靶向诱导细胞凋亡建立了独特的机会。虽然已经报道了几种小分子通过拮抗Hdm 2-p53相互作用来拯救肿瘤抑制因子，但这些药物由于在富含活性Hdmx的肿瘤中无效而显示出有限的应用范围。在这里，我们描述了使用的遗传选择系统和编码库的构象预组织的肽进行功能分析，揭示特定的识别功能，指导Hdm 2-p53和Hdmx-p53相互作用的拮抗作用的每个监管机构。最有效的线索的结构-活性关系分析确定了介导两个结构相关调节器的选择性识别的功能和结构元件，同时为进一步的活性优化提供了方便的起点。
Upregulation of structurally homologous oncoproteins Hdm2 and Hdmx has been linked to the depletion or inactivation of their common regulation target the tumor suppressor p53 protein leading to the progression of cancer. The restoration of the p53 function, rendered suppressed or dormant by these negative regulators, establishes, therefore, a unique opportunity for a targeted induction of apoptosis in cancers that retain wild-type p53. While several small molecules have been reported to rescue the tumor suppressor by antagonizing the Hdm2–p53 interaction, these agents displayed limited application scope by being ineffective in tumors enriched with active Hdmx. Here, we describe the use of a genetic selection system and encoded library of conformationally pre-organized peptides to perform functional profiling of each regulator revealing specific recognition features that guide the antagonism of Hdm2–p53 and Hdmx–p53 interactions. Structure–activity relationship analysis of the most effective leads identified functional and structural elements mediating selective recognition of the two structurally related regulators, while providing convenient starting points for further activity optimization.