PDK2-mediated alternative splicing switches Bnip3 from cell death to cell survival.
PDK2-mediated alternative splicing switches Bnip3 from cell death to cell survival.
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DOI：
10.1083/jcb.201504047
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发表时间：
2015-09-28
期刊：
影响因子：
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通讯作者：
Kirshenbaum LA
中科院分区：
文献类型：
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作者：
Gang H;Dhingra R;Lin J;Hai Y;Aviv Y;Margulets V;Hamedani M;Thanasupawat T;Leygue E;Klonisch T;Davie JR;Kirshenbaum LA
在缺氧条件下，由糖酵解酶PDK 2介导的癌细胞的存活特性与选择性剪接和死亡基因Bnip 3的新型同种型的产生强制性相关，Bnip 3抑制线粒体损伤并促进存活。在这里，我们描述了一种新的生存途径，可操作地链接的低氧诱导死亡蛋白Bcl-2 19-kD相互作用蛋白3（Bnip 3）的替代前mRNA剪接的独特糖酵解表型在癌细胞。虽然由外显子1-6编码的全长Bnip 3蛋白（Bnip 3FL）在正常细胞中表达为同种型并促进细胞死亡，但缺失外显子3的Bnip 3 mRNA的截短剪接变体（Bnip 3 Δ ex 3）优先在几种人类腺癌中表达并促进存活。通过抑制Panc-1细胞中的丙酮酸脱氢酶激酶亚型2（PDK 2）来相互抑制Bnip 3 Δ ex 3/Bnip 3FL亚型比率，快速诱导线粒体扰动和细胞死亡。本研究的发现揭示了一种新的生存途径，该途径通过PDK 2依赖性机制将癌细胞中独特的糖酵解表型与耐缺氧性功能性结合，该机制将Bnip 3从细胞死亡转换为存活。Bnip 3 Δ ex 3同种型的发现可能从根本上解释某些细胞如何抵抗Bnip 3并避免在缺氧期间死亡。
In hypoxia, the survival property of cancer cells mediated by the glycolytic enzyme PDK2 is obligatorily linked to alternative splicing and generation of a novel isoform of death gene Bnip3, which suppresses mitochondrial injury and promotes survival. Herein we describe a novel survival pathway that operationally links alternative pre-mRNA splicing of the hypoxia-inducible death protein Bcl-2 19-kD interacting protein 3 (Bnip3) to the unique glycolytic phenotype in cancer cells. While a full-length Bnip3 protein (Bnip3FL) encoded by exons 1–6 was expressed as an isoform in normal cells and promoted cell death, a truncated spliced variant of Bnip3 mRNA deleted for exon 3 (Bnip3Δex3) was preferentially expressed in several human adenocarcinomas and promoted survival. Reciprocal inhibition of the Bnip3Δex3/Bnip3FL isoform ratio by inhibiting pyruvate dehydrogenase kinase isoform 2 (PDK2) in Panc-1 cells rapidly induced mitochondrial perturbations and cell death. The findings of the present study reveal a novel survival pathway that functionally couples the unique glycolytic phenotype in cancer cells to hypoxia resistance via a PDK2-dependent mechanism that switches Bnip3 from cell death to survival. Discovery of the survival Bnip3Δex3 isoform may fundamentally explain how certain cells resist Bnip3 and avert death during hypoxia.