Journal of Biological Chemistry
Volume 290, Issue 37, 11 September 2015, Pages 22649-22661
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Molecular Bases of Disease
The Oncoprotein HBXIP Modulates the Feedback Loop of MDM2/p53 to Enhance the Growth of Breast Cancer*

https://doi.org/10.1074/jbc.M115.658468Get rights and content
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MDM2 and p53 form a negative feedback loop, in which p53 as a transcription factor positively regulates MDM2 and MDM2 negatively regulates tumor suppressor p53 through promoting its degradation. However, the mechanism of the feedback loop is poorly understood in cancers. We had reported previously that the oncoprotein hepatitis B X-interacting protein (HBXIP) is a key oncoprotein in the development of cancer. Thus, we supposed that HBXIP might be involved in the event. Here, we observed that the expression levels of HBXIP were positively correlated to those of MDM2 in clinical breast cancer tissues. Interestingly, HBXIP was able to up-regulate MDM2 at the levels of mRNA and protein in MCF-7 breast cancer cells. Mechanically, HBXIP increased the promoter activities of MDM2 through directly binding to p53 in the P2 promoter of MDM2. Strikingly, we identified that the acetyltransferase p300 was recruited by HBXIP to p53 in the promoter of MDM2. Moreover, we validated that HBXIP enhanced the p53 degradation mediated by MDM2. Functionally, the knockdown of HBXIP or/and p300 inhibited the proliferation of breast cancer cells in vitro, and the depletion of MDM2 or overexpression of p53 significantly blocked the HBXIP-promoted growth of breast cancer in vitro and in vivo. Thus, we concluded that highly expressed HBXIP accelerates the MDM2-mediated degradation of p53 in breast cancer through modulating the feedback loop of MDM2/p53, resulting in the fast growth of breast cancer cells. Our findings provide new insights into the mechanism of the acceleration of the MDM2/p53 feedback loop in the development of cancer.

breast cancer
mouse double minute 2 homolog (MDM2)
oncogene
p53
tumor
HBXIP
p300

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*

This work was supported by Grant 2015CB553905 from the National Basic Research Program of China (973 Program), Grants 81372186, 81272217, and 81272218 from the National Natural Science Foundation of China, and Grant 2014ZX0002002-005 from the Project for Prevention and Treatment of Key Infectious Diseases. The authors declare that they have no conflicts of interest with the contents of this article.