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学科主题: 药学
题名:
Vitamin E Facilitates the Inactivation of the Kinase Akt by the Phosphatase PHLPP1
作者: Huang, Po-Hsien1,2; Chuang, Hsiao-Ching1; Chou, Chih-Chien1; Wang, Huiling1,3; Lee, Su-Lin1; Yang, Hsiao-Ching4; Chiu, Hao-Chieh1; Kapuriya, Naval1; Wang, Dasheng1; Kulp, Samuel K.1; Chen, Ching-Shih1,2
刊名: SCIENCE SIGNALING
发表日期: 2013-03-19
DOI: 10.1126/scisignal.2003816
卷: 6, 期:267
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Biochemistry & Molecular Biology ; Cell Biology
研究领域[WOS]: Biochemistry & Molecular Biology ; Cell Biology
关键词[WOS]: PLECKSTRIN-HOMOLOGY-DOMAIN ; PROSTATE-CANCER CELLS ; ALPHA-TOCOPHEROL ; LIPID RAFTS ; INHIBITORS ; PTEN ; AKT/PKB ; PATHWAY ; GAMMA ; PHOSPHORYLATION
英文摘要:

Vitamin E is a fat-soluble vitamin with antioxidant properties. Tocopherols are the predominant form of vitamin E found in the diet and in supplements and have garnered interest for their potential cancer therapeutic and preventive effects, such as the dephosphorylation of Akt, a serine/threonine kinase with a pivotal role in cell growth, survival, and metabolism. Dephosphorylation of Akt at Ser(473) substantially reduces its catalytic activity and inhibits downstream signaling. We found that the mechanism by which alpha-tocopherol and gamma-tocopherol facilitate this site-specific dephosphorylation of Akt was mediated through the pleckstrin homology (PH) domain-dependent recruitment of Akt and PHLPP1 (PH domain leucine-rich repeat protein phosphatase, isoform 1) to the plasma membrane. We structurally optimized these tocopherols to obtain derivatives with greater in vitro potency and in vivo tumor-suppressive activity in two prostate xenograft tumor models. Binding affinities for the PH domains of Akt and PHLPP1 were greater than for other PH domain-containing proteins, which may underlie the preferential recruitment of these proteins to membranes containing tocopherols. Molecular modeling revealed the structural determinants of the interaction with the PH domain of Akt that may inform strategies for continued structural optimization. By describing a mechanism by which tocopherols facilitate the dephosphorylation of Akt at Ser(473), we provide insights into the mode of antitumor action of tocopherols and a rationale for the translational development of tocopherols into novel PH domain-targeted Akt inhibitors.

语种: 英语
所属项目编号: CA112250
项目资助者: NIH grant
WOS记录号: WOS:000316365000004
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/63809
Appears in Collections:北京大学药学院_化学生物学系_期刊论文

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作者单位: 1.Fu Jen Catholic Univ, Dept Chem, New Taipei City 24205, Taiwan
2.Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA
3.Natl Cheng Kung Univ, Inst Basic Med Sci, Tainan 701, Taiwan
4.Peking Univ, Sch Pharmaceut Sci, Dept Biol Chem, Hlth Sci Ctr, Beijing 100191, Peoples R China

Recommended Citation:
Huang, Po-Hsien,Chuang, Hsiao-Ching,Chou, Chih-Chien,et al. Vitamin E Facilitates the Inactivation of the Kinase Akt by the Phosphatase PHLPP1[J]. SCIENCE SIGNALING,2013,6(267).
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