Abstract
Genomic and proteomic profiling of human tumor samples and tumor-derived cell lines are essential for the realization of personalized therapy in oncology. Identification of the changes required for tumor initiation or maintenance will likely provide new targets for small-molecule and biological therapeutics. For example, inactivation of the p53 tumor suppressor pathway occurs in most human cancers. Although this can be due to frank p53 gene mutation, almost half of all cancers retain the wild-type p53 allele, indicating that the pathway is disabled by other means. Alternate mechanisms include deletion or epigenetic inactivation of the p53-positive regulator arf, methylation of the p53 promoter, or elevated expression of the p53 regulators Mdm2 and Mdmx. This review discusses current models of p53 regulation by Mdm2 and Mdmx and presents the rationale for design of future Mdmx-specific therapeutics based on our knowledge of its structure and biological functions.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Animals
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Cell Cycle Proteins
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Dimerization
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Gene Expression Regulation, Neoplastic
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Genes, p53*
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Humans
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Mice
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Mice, Transgenic
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Mutation
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Neoplasms / genetics*
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Neoplasms / therapy*
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / drug effects
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-mdm2 / drug effects
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Proto-Oncogene Proteins c-mdm2 / genetics*
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Transcription, Genetic
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Transcriptional Activation
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Cell Cycle Proteins
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MDM4 protein, human
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Nuclear Proteins
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2