Mammalian hepatitis B X-interacting protein (HBXIP) is an 18-kDa protein that regulates a large number of transcription factors such as TF-IID, E2F1, SP1, STAT3, c-Myc, and LXR by serving as an oncogenic transcription coactivator and plays an important role in the development of breast cancer. We previously showed that HBXIP as an oncoprotein could enhance the promoter activity of MDM2 through coactivating p53, promoting the MDM2 transcription in breast cancer. In this study we investigated the molecular mechanisms underlying the modulation of MDM2/p53 interaction by HBXIP in human breast cancer MCF-7 cells in vitro and in vivo. We showed that HBXIP could up-regulate MDM2 through inducing DNA methylation of miR-18b, thus suppressing the miR-18b expression, leading to the attenuation of p53 in breast cancer cells. In addition, HBXIP could promote the phosphorylation of MDM2 by increasing the level of pAKT and bind to pMDM2, subsequently enhancing the interaction between MDM2 and p53 for the down-regulation of p53 in breast cancer cells. In MCF-7 breast cancer xenograft nude mice, we also observed that overexpression of HBXIP promoted breast cancer growth through the miR-18b/MDM2 and pAKT/MDM2 pathways. In conclusion, oncoprotein HBXIP suppresses miR-18b to elevate MDM2 and activates pAKT to phosphorylate MDM2 for enhancing the interaction between MDM2 and p53, leading to p53 degradation in promotion of breast cancer growth. Our findings shed light on a novel mechanism of p53 down-regulation during the development of breast cancer.

中文翻译：

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癌蛋白HBXIP通过下调miR-18b / MDM2和pAKT / MDM2途径的p53促进人类乳腺癌的生长。

哺乳动物乙型肝炎X相互作用蛋白（HBXIP）是一种18 kDa的蛋白，可通过充当致癌转录共激活因子来调节大量转录因子，例如TF-IID，E2F1，SP1，STAT3，c-Myc和LXR。在乳腺癌的发展中起着重要作用。我们先前表明，HBXIP作​​为一种癌蛋白可以通过共激活p53来增强MDM2的启动子活性，从而促进乳腺癌中MDM2的转录。在这项研究中，我们研究了在体外和体内HBXIP调节人乳腺癌MCF-7细胞中MDM2 / p53相互作用的分子机制。我们表明，HBXIP可以通过诱导miR-18b的DNA甲基化来上调MDM2，从而抑制miR-18b的表达，从而导致乳腺癌细胞中p53的减弱。此外，HBXIP可以通过增加pAKT的水平来促进MDM2的磷酸化并与pMDM2结合，从而增强MDM2和p53之间的相互作用，从而下调乳腺癌细胞中的p53。在MCF-7乳腺癌异种移植裸鼠中，我们还观察到HBXIP的过表达通过miR-18b / MDM2和pAKT / MDM2途径促进了乳腺癌的生长。总之，癌蛋白HBXIP抑制miR-18b升高MDM2并激活pAKT磷酸化MDM2，从而增强MDM2与p53之间的相互作用，导致p53降解促进乳腺癌的生长。我们的发现揭示了乳腺癌发展过程中p53下调的新机制。随后增强了MDM2和p53之间的相互作用，从而下调了乳腺癌细胞中p53的表达。在MCF-7乳腺癌异种移植裸鼠中，我们还观察到HBXIP的过表达通过miR-18b / MDM2和pAKT / MDM2途径促进了乳腺癌的生长。总之，癌蛋白HBXIP抑制miR-18b升高MDM2并激活pAKT磷酸化MDM2，从而增强MDM2与p53之间的相互作用，导致p53降解促进乳腺癌的生长。我们的发现揭示了乳腺癌发展过程中p53下调的新机制。随后增强了MDM2和p53之间的相互作用，从而下调了乳腺癌细胞中p53的表达。在MCF-7乳腺癌异种移植裸鼠中，我们还观察到HBXIP的过表达通过miR-18b / MDM2和pAKT / MDM2途径促进了乳腺癌的生长。总之，癌蛋白HBXIP抑制miR-18b升高MDM2并激活pAKT磷酸化MDM2，从而增强MDM2与p53之间的相互作用，导致p53降解促进乳腺癌的生长。我们的发现揭示了乳腺癌发展过程中p53下调的新机制。癌蛋白HBXIP抑制miR-18b升高MDM2并激活pAKT磷酸化MDM2，从而增强MDM2与p53之间的相互作用，导致p53降解促进乳腺癌的生长。我们的发现揭示了乳腺癌发展过程中p53下调的新机制。癌蛋白HBXIP抑制miR-18b升高MDM2并激活pAKT磷酸化MDM2，从而增强MDM2和p53之间的相互作用，从而导致p53降解，从而促进乳腺癌的生长。我们的发现揭示了乳腺癌发展过程中p53下调的新机制。