A Strategy for Direct Chemical Activation of the Retinoblastoma Protein.
A Strategy for Direct Chemical Activation of the Retinoblastoma Protein.
复制标题
视网膜母细胞瘤蛋白的直接化学激活策略。
DOI：
10.1021/acschembio.6b00011
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发表时间：
2016
影响因子：
4
通讯作者：
Rubin,SethM
中科院分区：
文献类型：
--
作者：
Pye,CameronR;Bray,WalterM;Brown,EliseR;Burke,JasonR;Lokey,RScott;Rubin,SethM
The retinoblastoma (Rb) tumor suppressor protein negatively regulates cell proliferation by binding and inhibiting E2F transcription factors. Rb inactivation occurs in cancer cells upon cyclin-dependent kinase (Cdk) phosphorylation, which induces E2F release and activation of cell cycle genes. We present a strategy for activating phosphorylated Rb with molecules that bind Rb directly and enhance affinity for E2F. We developed a fluorescence polarization assay that can detect the effect of exogenous compounds on modulating affinity of Rb for the E2F transactivation domain. We found that a peptide capable of disrupting the compact inactive Rb conformation increases affinity of the repressive Rb–E2F complex. Our results demonstrate the feasibility of discovering novel molecules that target the cell cycle and proliferation through directly targeting Rb rather than upstream kinase activity.
