Charge modification at multiple C-terminal lysine residues regulates p53 oligomerization and its nucleus-cytoplasm trafficking
Charge modification at multiple C-terminal lysine residues regulates p53 oligomerization and its nucleus-cytoplasm trafficking
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DOI：
10.1074/jbc.m505772200
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发表时间：
2006-01-20
影响因子：
4.8
通讯作者：
Yao, TP
中科院分区：
文献类型：
--
作者：
Kawaguchi, Y;Ito, A;Yao, TP
肿瘤抑制因子p53的基础水平由MDM 2介导的特定赖氨酸的泛素化调节，这导致p53核输出和降解。然而，在p53激活后，这些赖氨酸被p300/CREB结合蛋白乙酰化。在这里，我们报告了一个意想不到的发现，p300介导的乙酰化也调节p53的亚细胞定位，并可以促进p53的细胞质定位。这种活性不依赖于MDM 2，但需要p53核输出信号和p300对多个赖氨酸的乙酰化。从机制上讲，我们发现这些赖氨酸中的最少四个转化为丙氨酸而不是丙氨酸模拟p300介导的p53核输出，并且这些赖氨酸中和突变有效地防止p53四聚化，从而暴露寡聚化调节的核输出信号。我们的研究提出了一个阈值机制，乙酰化程度调节p53细胞核-细胞质运输通过中和赖氨酸依赖的电荷补丁，这反过来又控制寡聚化依赖的p53核输出。
The basal level of the tumor suppressor p53 is regulated by MDM2-mediated ubiquitination at specific lysines, which leads to p53 nuclear export and degradation. Upon p53 activation, however, these lysines become acetylated by p300/CREB-binding protein. Here we have reported an unexpected finding that p300-mediated acetylation also regulates p53 subcellular localization and can promote cytoplasmic localization of p53. This activity is independent of MDM2 but requires a p53 nuclear export signal and acetylation of multiple lysines by p300. Mechanistically, we showed that conversion of a minimal four of these lysines to alanines but not arginines mimics p300-mediated p53 nuclear export, and these lysine-neutralizing mutations effectively prevent p53 tetramerization, thus exposing the oligomerization-regulated nuclear export signal. Our study suggested a threshold mechanism whereby the degree of acetylation regulates p53 nucleus-cytoplasm trafficking by neutralizing a lysine-dependent charge patch, which in turn, controls oligomerization-dependent p53 nuclear export.