title: The oncoprotein HBXIP modulates the feedback loop of MDM2/p53 to enhance the growth of breast cancer.
abstract: 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.
authors.affiliation: From the Department of Biochemistry and.
authors.forename: Hang
authors.initials: H
authors.lastname: Li
authors.affiliation: From the Department of Biochemistry and.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: From the Department of Biochemistry and.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: From the Department of Biochemistry and.
authors.forename: Runping
authors.initials: R
authors.lastname: Fang
authors.affiliation: From the Department of Biochemistry and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
authors.affiliation: From the Department of Biochemistry and.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Cai
authors.affiliation: the Department of Cancer Research, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Yuen
authors.initials: Y
authors.lastname: Gao
authors.affiliation: From the Department of Biochemistry and.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Li
authors.affiliation: the Department of Cancer Research, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China zhangxd@nankai.edu.cn.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Department of Biochemistry and yelihong@nankai.edu.cn.
authors.forename: Lihong
authors.initials: L
authors.lastname: Ye
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C110719:LAMTOR5 protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: HBXIP; breast cancer; mouse double minute 2 homolog (MDM2); oncogene; p300; p53; tumor