Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice
Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice
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DOI：
10.1038/onc.2008.76
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发表时间：
2008-07-17
期刊：
影响因子：
8
通讯作者：
Saya, H.
中科院分区：
文献类型：
--
作者：
Zhang, D.;Shimizu, T.;Saya, H.
Aurora A有丝分裂激酶经常在各种人类癌症中过表达，并被广泛认为是一种癌蛋白。然而，Aurora A在体内诱导恶性肿瘤的细胞背景仍不清楚。我们以前报道了一个小鼠模型，其中过度表达人类极光A在乳腺导致小的增生性变化，但不是恶性的，因为诱导p53依赖性细胞凋亡。为了研究Aurora A相关肿瘤发生所需的其他因素，我们建立了一种新的Aurora A过表达小鼠模型，该模型缺乏p53。我们在这里提出的证据表明，极光A在原代小鼠胚胎成纤维细胞（MEFs），缺乏p53覆盖有丝分裂后检查点，并导致形成多核多倍体细胞。在p53缺陷小鼠乳腺中诱导Aurora A过表达导致癌前病变的发展，这些癌前病变在组织学上与人类乳腺组织中的非典型导管增生相似，并显示细胞衰老和p16表达增加。我们进一步观察到Aurora A过表达后p53缺陷的原代MEFs中的DNA损伤。我们的研究结果表明，Aurora A在乳腺中的过度表达是不足以在p53缺陷小鼠恶性肿瘤的发展，因为细胞衰老的诱导。在Aurora A过表达小鼠模型中，p53和p16在预防乳腺肿瘤发生中均至关重要。
Aurora A mitotic kinase is frequently overexpressed in various human cancers and is widely considered to be an oncoprotein. However, the cellular contexts in which Aurora A induces malignancy in vivo are still unclear. We previously reported a mouse model in which overexpression of human Aurora A in the mammary gland leads to small hyperplastic changes but not malignancy because of the induction of p53-dependent apoptosis. To study the additional factors required for Aurora A-associated tumorigenesis, we generated a new Aurora A overexpression mouse model that lacks p53. We present evidence here that Aurora A overexpression in primary mouse embryonic fibroblasts (MEFs) that lack p53 overrides postmitotic checkpoint and leads to the formation of multinucleated polyploid cells. Induction of Aurora A overexpression in the mammary glands of p53-deficient mice resulted in development of precancerous lesions that were histologically similar to atypical ductal hyperplasia in human mammary tissue and showed increased cellular senescence and p16 expression. We further observed DNA damage in p53-deficient primary MEFs after Aurora A overexpression. Our results suggest that Aurora A overexpression in mammary glands is insufficient for the development of malignant tumors in p53-deficient mice because of the induction of cellular senescence. Both p53 and p16 are critical in preventing mammary gland tumorigenesis in the Aurora A overexpression mouse model.