PIM1 induces cellular senescence through phosphorylation of UHRF1 at Ser311
PIM1 induces cellular senescence through phosphorylation of UHRF1 at Ser311
复制标题
PIM1 通过 UHRF1 Ser311 磷酸化诱导细胞衰老
DOI：
10.1038/onc.2017.96
复制
发表时间：
2017-08-24
期刊：
影响因子：
8
通讯作者：
Mao, Z.
中科院分区：
文献类型：
--
作者：
Yang, J.;Liu, K.;Mao, Z.
PIM1是一种原癌基因，编码一种丝氨酸/苏氨酸蛋白激酶，调节细胞的增殖、存活、分化和凋亡。以往的报道表明，PIM1的过度表达可以诱导细胞衰老。然而，这一过程背后的分子机制尚不完全清楚。在这里，我们报道了uhrf1是PIM1激酶的一种新底物，它可以在Ser311处被磷酸化，从而促进其降解。我们的数据表明，PIM1使uhrf1不稳定，导致DNA低甲基化，从而导致基因组不稳定，p16表达增加，继而诱导细胞衰老。综上所述，我们的结果提示uhrf1的下调是PIM1介导的细胞衰老的一个重要机制。
PIM1 is a proto-oncogene, encoding a serine/threonine protein kinase that regulates cell proliferation, survival, differentiation and apoptosis. Previous reports suggest that overexpression of PIM1 can induce cellular senescence. However, the molecular mechanism underlying this process is not fully understood. Here we report that UHRF1 is a novel substrate of PIM1 kinase, which could be phosphorylated at Ser311 and therefore promoted to degradation. Our data demonstrates that PIM1 destabilizes UHRF1, leading to DNA hypomethylation, which consequently results in genomic instability, increased p16 expression and subsequent induction of cellular senescence. Taken together, our results suggest that down-regulation of UHRF1 is an important mechanism of PIM1-mediated cellular senescence.