Tumor suppressor SMAR1 activates and stabilizes p53 through its arginine-serine-rich motif (Publication with Expression of Concern. See vol. 294, pg. 17708, 2019) (Withdrawn Publication. See vol. 295, pg. 3390, 2020)
Tumor suppressor SMAR1 activates and stabilizes p53 through its arginine-serine-rich motif (Publication with Expression of Concern. See vol. 294, pg. 17708, 2019) (Withdrawn Publication. See vol. 295, pg. 3390, 2020)
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DOI：
10.1074/jbc.m413200200
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发表时间：
2005-04-22
影响因子：
4.8
通讯作者：
Chattopadhyay, S
中科院分区：
文献类型：
--
作者：
Jalota, A;Singh, K;Chattopadhyay, S
各种应激和 DNA 损伤剂通过翻译后修饰触发 p53 的转录活性，使其成为控制细胞增殖和凋亡的全局调节开关。之前我们已经证明新型 MAR 相关蛋白 SMAR1 与 p53 相互作用。在这里，我们描绘了 SMAR1 的最小结构域（富含精氨酸-丝氨酸的结构域），它被蛋白激酶 C 家族蛋白磷酸化，负责细胞核内 p53 的相互作用、激活和稳定。 SMAR1 介导的 p53 稳定是通过抑制 Mdm2 介导的 p53 降解来实现的。我们还证明，这种富含精氨酸-丝氨酸（RS）的结构域可以触发决定细胞命运的各种细胞周期调节蛋白。此外，使用小干扰RNA的表型敲低实验表明，SMAR1是p53激活和核保留所必需的。 SMAR1转基因小鼠胸腺中磷酸化p53的水平显着增加，显示出SMAR1表达的体内显着性。这是第一份证明 MAR 结合蛋白 SMAR1 调节 p53 活性的作用机制的报告，p53 通常被称为“基因组的守护者”。
Various stresses and DNA-damaging agents trigger transcriptional activity of p53 by post-translational modifications, making it a global regulatory switch that controls cell proliferation and apoptosis. Earlier we have shown that the novel MAR-associated protein SMAR1 interacts with p53. Here we delineate the minimal domain of SMAR1 ( the arginine-serine-rich domain) that is phosphorylated by protein kinase C family proteins and is responsible for p53 interaction, activation, and stabilization within the nucleus. SMAR1-mediated stabilization of p53 is brought about by inhibiting Mdm2-mediated degradation of p53. We also demonstrate that this arginine-serine (RS)-rich domain triggers the various cell cycle modulating proteins that decide cell fate. Furthermore, phenotypic knock-down experiments using small interfering RNA showed that SMAR1 is required for activation and nuclear retention of p53. The level of phosphorylated p53 was significantly increased in the thymus of SMAR1 transgenic mice, showing in vivo significance of SMAR1 expression. This is the first report that demonstrates the mechanism of action of the MAR-binding protein SMAR1 in modulating the activity of p53, often referred to as the "guardian of the genome."