Natural Diterpenoid Compound Elevates Expression of Bim Protein, Which Interacts with Antiapoptotic Protein Bcl-2, Converting It to Proapoptotic Bax-like Molecule
Zhao, Lixia2,3; He, Feng4; Liu, Haiyang1; Zhu, Yushan2,3; Tian, Weili2,3; Gao, Ping2,3; He, Hongping1; Yue, Wen2,3; Lei, Xiaobo2,3; Ni, Biyun2,3; Wang, Xiaohui2,3; Jin, Haijing2,3; Hao, Xiaojiang1; Lin, Jialing4; Chen, Quan2,3
2012-01-06
Source PublicationJOURNAL OF BIOLOGICAL CHEMISTRY
Volume287Issue:2Pages:1054-1065
AbstractOverwhelming evidence indicates that Bax and Bak are indispensable for mediating cytochrome c release from mitochondria during apoptosis. Here we report a Bax/Bak-independent mechanism of cytochrome c release and apoptosis. We identified a natural diterpenoid compound that induced apoptosis in bax/bak double knock-out murine embryonic fibroblasts and substantially reduced the tumor growth from these cells implanted in mice. Treatment with the compound significantly increased expression of Bim, which migrated to mitochondria, altering the conformation of and forming oligomers with resident Bcl-2 to induce cytochrome c release and caspase activation. Importantly, purified Bim and Bcl-2 proteins cooperated to permeabilize a model mitochondrial outer membrane; this was accompanied by oligomerization of these proteins and deep embedding of Bcl-2 in the membrane. Therefore, the diterpenoid compound induces a structural and functional conversion of Bcl-2 through Bim to permeabilize the mitochondrial outer membrane, thereby inducing apoptosis independently of Bax and Bak. Because Bcl-2 family proteins play important roles in cancer development and relapse, this novel cell death mechanism can be explored for developing more effective anticancer therapeutics.
DOI10.1074/jbc.M111.264481
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemistry & Molecular Biology
WOS IDWOS:000299170300022
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Document Type期刊论文
Identifierhttp://ir.kib.ac.cn/handle/151853/20452
Collection植物化学与西部植物资源持续利用国家重点实验室
Affiliation1.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources W China, Kunming 650204, Peoples R China
2.Chinese Acad Sci, State Key Lab Biomembrane & Membrane Biotechnol, Inst Zool, Joint Lab Apoptosis & Mitochondrial Biol, Beijing 100101, Peoples R China
3.Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China
4.Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73126 USA
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Zhao, Lixia,He, Feng,Liu, Haiyang,et al. Natural Diterpenoid Compound Elevates Expression of Bim Protein, Which Interacts with Antiapoptotic Protein Bcl-2, Converting It to Proapoptotic Bax-like Molecule[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2012,287(2):1054-1065.
APA Zhao, Lixia.,He, Feng.,Liu, Haiyang.,Zhu, Yushan.,Tian, Weili.,...&Chen, Quan.(2012).Natural Diterpenoid Compound Elevates Expression of Bim Protein, Which Interacts with Antiapoptotic Protein Bcl-2, Converting It to Proapoptotic Bax-like Molecule.JOURNAL OF BIOLOGICAL CHEMISTRY,287(2),1054-1065.
MLA Zhao, Lixia,et al."Natural Diterpenoid Compound Elevates Expression of Bim Protein, Which Interacts with Antiapoptotic Protein Bcl-2, Converting It to Proapoptotic Bax-like Molecule".JOURNAL OF BIOLOGICAL CHEMISTRY 287.2(2012):1054-1065.
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