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PICT1 is critical for regulating the Rps27a-Mdm2-p53 pathway by microtubule polymerization inhibitor against cervical cancer
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 4.6 ) Pub Date : 2021-06-22 , DOI: 10.1016/j.bbamcr.2021.119084
Huai Wang 1 , Junjie Zhao 1 , Jian Yang 1 , Shukun Wan 1 , Yihong Fu 1 , Xinlu Wang 1 , Tong Zhou 1 , Zhongwei Zhang 1 , Jiaomei Shen 2
Affiliation  

In our previous study, it showed that P-3F, a podophyllotoxin derivative, causes the increased level of p53 expression by enhancing p53 stability, resulting from blockage of the Mdm2-p53 feedback loop via nucleolus-to-nucleoplasm translocation of Rps27a in human cervical cancer HeLa cell line. However, the mechanism of regulating Rps27a localization remains to be studied. In the current study, it has been demonstrated that the level of protein interacting with carboxyl terminus 1 (PICT1), originally identified as a tumor suppressor, was decreased in a concentration-dependent manner in response to P-3F, leading to inhibition of human cervical cancer cell lines proliferation. Also remarkably, reduction of serine phosphorylation of STMN1 at position 16 induced by P-3F was required in the downregulation of PICT1, in which p53 activity was likely to be directly involved. Note as well that, PICT1 also played an important role in p53 stability enhancement by inhibiting Mdm2-mediated p53 ubiquitination due to Rps27a translocation from the nucleolus to the nucleoplasm to interact with Mdm2 following treatment with P-3F. Collectively, these findings indicated that P-3F, a microtubule polymerization inhibitor, promotes the decreased level of PICT1 expression, which is critical for regulating the Rps27a-Mdm2-p53 pathway against cervical cancer.



中文翻译:

PICT1对于通过微管聚合抑制剂调节Rps27a-Mdm2-p53通路对宫颈癌至关重要

在我们之前的研究中,它表明P-3F是一种鬼臼毒素衍生物,通过增强 p53 稳定性导致 p53 表达水平增加,这是由于 Mdm2-p53 反馈回路通过 Rps27a 在人宫颈中的核仁到核质易位被阻断。癌症 HeLa 细胞系。然而,调控 Rps27a 定位的机制仍有待研究。在目前的研究中,已经证明与羧基末端 1 (PICT1) 相互作用的蛋白质水平,最初被确定为肿瘤抑制因子,响应P-3F以浓度依赖性方式降低,导致抑制人类宫颈癌细胞系增殖。同样值得注意的是,P-3F诱导的 STMN1 16 位丝氨酸磷酸化的减少PICT1 的下调是必需的,其中 p53 活性可能直接参与。还要注意的是,PICT1 还通过抑制 Mdm2 介导的 p53 泛素化在 p53 稳定性增强中发挥重要作用,这是由于 Rps27a 在用P-3F处理后从核仁到核质的易位与 Mdm2 相互作用。总的来说,这些发现表明P-3F是一种微管聚合抑制剂,可促进 PICT1 表达水平的降低,这对于调节 Rps27a-Mdm2-p53 通路对抗宫颈癌至关重要。

更新日期:2021-06-28
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