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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Overexpression of Separase induces aneuploidy and mammary tumorigenesis
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Overexpression of Separase induces aneuploidy and mammary tumorigenesis

机译：Separase的过表达诱导非整倍性和乳腺肿瘤发生

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摘要

Separase is an endopeptidase that separates sister chromatids by cleaving cohesin Rad21 during the metaphase-to-anaphase transition. Conditional expression of Separase in tetracycline-inducible diploid FSK3 mouse mammary epithelial cells with both p53 WT and mutant (Ser-233-234) alleles of unknown physiological significance develops aneuploidy within 5 days of Separase induction in vitro. Overexpression of Separase induces premature separation of chromatids, lagging chromosomes, and anaphase bridges. In an in vivo mouse mammary transplant model, induction of Separase expression in the transplanted FSK3 cells for 3-4 weeks results in the formation of aneuploid tumors in the mammary gland. Xenograft studies combined with histological and cytogenetic analysis reveal that Separase-induced tumors are clonal in their genomic complements and have a mesenchymal phenotype suggestive of an epithelial-mesenchymal transition. Induction of Separase resulted in trisomies for chromosomes 8,15, and 17; monosomy for chromosome 10; and amplification of the distal region of chromosomes 8 and 11. Separase protein is found to be significantly overexpressed in human breast tumors compared with matched normal tissue. These results collectively suggest that Separase is an oncogene, whose overexpression alone in mammary epithelial cells is sufficient to induce aneuploidy and tumorigenesis in a p53 mutant background.
机译：Separase是一种内肽酶，通过在中期到后期过渡过程中裂解黏附素Rad21来分离姐妹染色单体。在具有未知生理学意义的p53 WT和突变（Ser-233-234）等位基因的四环素诱导的二倍体FSK3小鼠乳腺上皮细胞中，Separase的条件表达在体外Separase诱导后5天内发展为非整倍性。 Separase的过表达诱导染色单体，落后的染色体和后期桥的过早分离。在体内小鼠乳腺移植模型中，在移植的FSK3细胞中诱导Separase表达3-4周会导致在乳腺中形成非整倍性肿瘤。异种移植研究与组织学和细胞遗传学分析相结合，揭示了Separase诱导的肿瘤在其基因组互补基因上是克隆的，并具有提示上皮-间质转化的间充质表型。分离酶的诱导导致染色体8、15和17的三体性；第10号染色体的单体；与匹配的正常组织相比，发现分离酶蛋白在人乳腺肿瘤中显着过表达，并扩增了8号和11号染色体的远端区域。这些结果共同表明Separase是一种癌基因，仅在乳腺上皮细胞中的过表达就足以在p53突变体背景中诱导非整倍性和肿瘤发生。

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