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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation.
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Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation.

机译：Snf5肿瘤抑制剂的失活刺激细胞周期进程，并在致癌转化中与p53丢失协同作用。

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摘要

Snf5 (Ini1/Baf47/Smarcb1), a core member of the Swi/Snf chromatin remodeling complex, is a potent tumor suppressor whose mechanism of action is largely unknown. Biallelic loss of Snf5 leads to the onset of aggressive cancers in both humans and mice. We have developed an innovative and widely applicable analytical technique for cross-species validation of cancer models and show that the gene expression profiles of our Snf5 murine models closely resemble those of human Snf5-deficient rhabdoid tumors. We exploit this system to produce what we believe to be the first report documenting the effects on gene expression of inactivating a Swi/Snf subunit in normal mammalian cells and to identify the transcriptional pathways regulated by Snf5. We demonstrate that the tumor suppressor activity of Snf5 depends on its regulation of cell cycle progression; Snf5 inactivation leads to aberrant up-regulation of E2F targets and increased levels of p53 that are accompanied by apoptosis, polyploidy, and growth arrest. Further, conditional mouse models demonstrate that inactivation of p16Ink4a or Rb (retinoblastoma) does not accelerate tumor formation in Snf5 conditional mice, whereas mutation of p53 leads to a dramatic acceleration of tumor formation.
机译：Snf5（Ini1 / Baf47 / Smarcb1）是Swi / Snf染色质重塑复合体的核心成员，是一种有效的抑癌剂，其作用机理尚不清楚。 Snf5的双等位基因缺失会导致人类和小鼠的侵袭性癌症发作。我们已经开发出一种创新的且广泛适用的分析技术，用于癌症模型的跨物种验证，并且表明我们的Snf5鼠模型的基因表达谱与人类Snf5缺陷型横纹肌瘤的基因表达谱非常相似。我们利用该系统产生我们认为是第一份报告，该报告记录了正常哺乳动物细胞中Swi / Snf亚基失活对基因表达的影响，并确定了Snf5调控的转录途径。我们证明，Snf5的肿瘤抑制活性取决于其对细胞周期进程的调控。 Snf5失活导致E2F靶标异常上调和p53水平升高，并伴有凋亡，多倍体性和生长停滞。此外，条件小鼠模型证明p16Ink4a或Rb（成视网膜细胞瘤）的失活不会加速Snf5条件小鼠的肿瘤形成，而p53的突变会导致肿瘤形成的显着加速。

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