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DOI | 10.1126/science.aaw2106 |
p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition | |
Guiley, Keelan Z.1,2,3; Stevenson, Jack W.2,3; Lou, Kevin2,3; Barkovich, Krister J.2,3; Kumarasamy, Vishnu4; Wijeratne, Tilini U.1; Bunch, Katharine L.1; Tripathi, Sarvind1; Knudsen, Erik S.4; Witkiewicz, Agnieszka K.4; Shokat, Kevan M.2,3; Rubin, Seth M.1 | |
2019-12-13 | |
发表期刊 | SCIENCE |
ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2019 |
卷号 | 366期号:6471页码:1330-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | The p27 protein is a canonical negative regulator of cell proliferation and acts primarily by inhibiting cyclin-dependent kinases (CDKs). Under some circumstances, p27 is associated with active CDK4, but no mechanism for activation has been described. We found that p27, when phosphorylated by tyrosine kinases, allosterically activated CDK4 in complex with cyclin D1 (CDK4-CycD1). Structural and biochemical data revealed that binding of phosphorylated p27 (phosp27) to CDK4 altered the kinase adenosine triphosphate site to promote phosphorylation of the retinoblastoma tumor suppressor protein (Rb) and other substrates. Surprisingly, purified and endogenous phosp27-CDK4-CycD1 complexes were insensitive to the CDK4-targeting drug palbociclib. Palbociclib instead primarily targeted monomeric CDK4 and CDK6 (CDK4/6) in breast tumor cells. Our data characterize phosp27-CDK4-CycD1 as an active Rb kinase that is refractory to clinically relevant CDK4/6 inhibitors. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000502802300047 |
WOS关键词 | CDK INHIBITORS ; CRYSTAL-STRUCTURE ; STRUCTURAL BASIS ; P27(KIP1) ; CANCER ; PROTEIN ; PHOSPHORYLATION ; MECHANISM ; RECRUITMENT ; COMPLEXES |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/226436 |
专题 | 环境与发展全球科技态势 |
作者单位 | 1.Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA; 2.Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA; 3.Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA; 4.Roswell Park Canc Ctr, Ctr Personalized Med, Buffalo, NY 14263 USA |
推荐引用方式 GB/T 7714 | Guiley, Keelan Z.,Stevenson, Jack W.,Lou, Kevin,et al. p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition[J]. SCIENCE,2019,366(6471):1330-+. |
APA | Guiley, Keelan Z..,Stevenson, Jack W..,Lou, Kevin.,Barkovich, Krister J..,Kumarasamy, Vishnu.,...&Rubin, Seth M..(2019).p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition.SCIENCE,366(6471),1330-+. |
MLA | Guiley, Keelan Z.,et al."p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition".SCIENCE 366.6471(2019):1330-+. |
条目包含的文件 | 条目无相关文件。 |
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