title: Natural diterpenoid compound elevates expression of Bim protein, which interacts with antiapoptotic protein Bcl-2, converting it to proapoptotic Bax-like molecule.
abstract: Overwhelming 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.
authors: Joint Laboratory of Apoptosis and Mitochondrial Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Lixia
authors: L
authors: Zhao
authors: Feng
authors: F
authors: He
authors: Haiyang
authors: H
authors: Liu
authors: Yushan
authors: Y
authors: Zhu
authors: Weili
authors: W
authors: Tian
authors: Ping
authors: P
authors: Gao
authors: Hongping
authors: H
authors: He
authors: Wen
authors: W
authors: Yue
authors: Xiaobo
authors: X
authors: Lei
authors: Biyun
authors: B
authors: Ni
authors: Xiaohui
authors: X
authors: Wang
authors: Haijing
authors: H
authors: Jin
authors: Xiaojiang
authors: X
authors: Hao
authors: Jialing
authors: J
authors: Lin
authors: Quan
authors: Q
authors: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D002461:Cell Line, Transformed; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D051336:Mitochondrial Membranes / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C494827:Bax protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D004224:Diterpenes; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c