Castedo Maria, Coquelle Arnaud, Vivet Sonia, Vitale Ilio, Kauffmann Audrey, Dessen Philippe, Pequignot Marie O, Casares Noelia, Valent Alexandre, Mouhamad Shahul, Schmitt Elise, Modjtahedi Nazanine, Vainchenker William, Zitvogel Laurence, Lazar Vladimir, Garrido Carmen, Kroemer Guido
CNRS, UMR8125, Institut Gustave Roussy, Villejuif, France.
EMBO J. 2006 Jun 7;25(11):2584-95. doi: 10.1038/sj.emboj.7601127. Epub 2006 May 4.
Tetraploidy can result in cancer-associated aneuploidy. As shown here, freshly generated tetraploid cells arising due to mitotic slippage or failed cytokinesis are prone to undergo Bax-dependent mitochondrial membrane permeabilization and subsequent apoptosis. Knockout of Bax or overexpression of Bcl-2 facilitated the survival of tetraploid cells at least as efficiently as the p53 or p21 knockout. When tetraploid cells were derived from diploid p53 and Bax-proficient precursors, such cells exhibited an enhanced transcription of p53 target genes. Tetraploid cells exhibited an enhanced rate of spontaneous apoptosis that could be suppressed by inhibition of p53 or by knockdown of proapoptotic p53 target genes such as BBC3/Puma, GADD45A and ferredoxin reductase. Unexpectedly, tetraploid cells were more resistant to DNA damaging agents (cisplatin, oxaliplatin and camptothecin) than their diploid counterparts, and this difference disappeared upon inhibition of p53 or knockdown of p53-inducible ribonucleotide reductase. Tetraploid cells were also more resistant against UVC and gamma-irradiation. These data indicate the existence of p53-dependent alterations in apoptosis regulation in tetraploid cells.
四倍体可导致癌症相关的非整倍体。如此处所示，由于有丝分裂滑脱或胞质分裂失败而新产生的四倍体细胞易于发生Bax依赖的线粒体膜通透性改变及随后的凋亡。敲除Bax或过表达Bcl-2促进四倍体细胞存活的效率至少与敲除p53或p21一样高。当四倍体细胞来源于二倍体p53和Bax功能正常的前体细胞时，这些细胞表现出p53靶基因转录增强。四倍体细胞表现出自发性凋亡率增加，可通过抑制p53或敲低促凋亡p53靶基因如BBC3/Puma、GADD45A和铁氧化还原蛋白还原酶来抑制。出乎意料的是，四倍体细胞比其二倍体对应细胞对DNA损伤剂（顺铂、奥沙利铂和喜树碱）更具抗性，并且这种差异在抑制p53或敲低p53诱导的核糖核苷酸还原酶后消失。四倍体细胞对紫外线C和γ射线也更具抗性。这些数据表明四倍体细胞中存在p53依赖的凋亡调节改变。
