Down-regulation of LATS kinases alters p53 to promote cell migration.
Down-regulation of LATS kinases alters p53 to promote cell migration.
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DOI：
10.1101/gad.268185.115
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发表时间：
2015-11-15
影响因子：
10.5
通讯作者：
Oren M
中科院分区：
文献类型：
--
作者：
Furth N;Bossel Ben-Moshe N;Pozniak Y;Porat Z;Geiger T;Domany E;Aylon Y;Oren M
在这项研究中，Furth等人鉴定了p53与LATS 1和LATS 2激酶之间的新联系，LATS 1和LATS 2激酶是Hippo肿瘤抑制途径的核心成分。他们表明，LATS 1和LATS 2在非转化乳腺上皮细胞中的沉默改变了p53的功能，导致p53构象和转录输出部分改变，为肿瘤细胞中p53的调控提供了新的见解。p53是一种重要的肿瘤抑制因子，也是对抗癌症的主要屏障。我们现在报道，在非转化的乳腺上皮细胞中，Hippo通路肿瘤抑制因子LATS 1和LATS 2的沉默降低了p53磷酸化，并增加了其与p52 NF-κB亚基的结合。此外，它部分地改变了p53的构象和转录输出，使其处于与癌症相关的p53突变体相似的状态，并赋予p53促进细胞迁移的能力。值得注意的是，LATS 1和LATS 2在乳腺癌中经常下调;我们认为这种下调可能通过将p53从肿瘤抑制因子转化为肿瘤促进因子而使癌症受益。
In this study, Furth et al. identify a novel link between p53 and the LATS1 and LATS2 kinases, core components of the Hippo tumor suppressor pathway. They show that silencing of LATS1 and LATS2 in nontransformed mammary epithelial cells changes p53 function, resulting in a partially altered p53 conformation and transcriptional output, providing novel insight into the regulation of p53 in tumor cells. p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in nontransformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-κB subunit. Moreover, it partly shifts p53's conformation and transcriptional output toward a state resembling cancer-associated p53 mutants and endows p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are frequently down-regulated in breast cancer; we propose that such down-regulation might benefit cancer by converting p53 from a tumor suppressor into a tumor facilitator.