Abstract
The tumor suppressor gene p53 is often inactivated in breast cancer cells due to gene mutation or overexpression of its repressors (such as murine double minute 2 and murine double minute X). Inhibitors of murine double minute 2 (MDM2) and murine double minute X (MDMX) could lead to tumor suppression by restoration of p53 activity and such an approach is a promising strategy for future control of breast cancer. This study aimed to investigate the feasibility of the recombinant MDM2 and MDMX inhibitory protein in control of breast cancer in vitro. A cell-permeable dual-target MDM2/MDMX inhibitory protein was expressed in E. coli and incubated with p53 wild-type breast cancer cells. The data showed that this recombinant MDM2/MDMX inhibitory protein reduced the viability of MCF-7 and ZR-75-30 breast cancer cell lines and promoted cell cycle arrest and apoptosis by activation and stabilization of the p53 protein. Mechanistically, this MDM2/MDMX inhibitory protein increased the expression of p21, Bax and puma proteins, and inhibitory expression of MDM2 and MDMX proteins. This recombinant protein showed a better in vitro effect than that of nutlin-3α, a small molecule MDM2 inhibitor. The data further support the hypothesis that targeting of the p53 gene pathway could effectively control breast cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / genetics*
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Apoptosis Regulatory Proteins / biosynthesis
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Breast Neoplasms / metabolism
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Cell Cycle Checkpoints / physiology
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Survival / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
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Female
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Humans
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Imidazoles / metabolism
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MCF-7 Cells
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Nuclear Proteins* / antagonists & inhibitors
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Nuclear Proteins* / genetics
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Nuclear Proteins* / metabolism
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Piperazines / metabolism
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Proto-Oncogene Proteins c-mdm2* / antagonists & inhibitors
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Proto-Oncogene Proteins c-mdm2* / genetics
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Proto-Oncogene Proteins c-mdm2* / metabolism
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Proto-Oncogene Proteins* / antagonists & inhibitors
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Proto-Oncogene Proteins* / biosynthesis
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Proto-Oncogene Proteins* / genetics
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Proto-Oncogene Proteins* / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism*
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Tumor Suppressor Protein p53 / biosynthesis
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Tumor Suppressor Protein p53 / metabolism*
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bcl-2-Associated X Protein / biosynthesis
Substances
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Imidazoles
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MDM4 protein, human
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Nuclear Proteins
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Piperazines
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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Tumor Suppressor Protein p53
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bcl-2-Associated X Protein
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nutlin 3
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2