Abstract
Differentially from other kinds of Ras, oncogenic K-Ras, which is mutated approximately 30% of human cancer, does not induce apoptosis and senescence. Here, we provide the evidence that oncogenic K-Ras abrogates p53 function and expression through induction of Ataxia telangiectasia-mutated and Rad3-related mediated Snail stabilization. Snail directly binds to DNA binding domain of p53 and diminishes the tumor-suppressive function of p53. Thus, elimination of Snail through si-RNA can induce p53 in K-Ras-mutated cells, whereas Snail and mutant K-Ras can suppress p53 in regardless of K-Ras status. Chemicals, isolated from inhibitor screening of p53-Snail binding, can block the Snail-mediated p53 suppression and enhance the expression of p53 as well as the transcriptional activity of p53 in an oncogenic K-Ras-dependent manner. Among the chemicals, two are very similar in structure. These results can answer why K-Ras can coexist with wild type p53 and propose the Snail-p53 binding as the new therapeutic target for K-Ras-mutated cancers including pancreatic, lung, and colon cancers.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / physiology
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Cells, Cultured
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Down-Regulation / drug effects
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Drug Design
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Drug Screening Assays, Antitumor
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Gene Expression Regulation, Neoplastic
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Genes, ras / physiology*
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HCT116 Cells
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Humans
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Male
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Mice
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Models, Biological
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Neoplasms / drug therapy
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Neoplasms / genetics
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Protein Binding / drug effects
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Protein Binding / physiology
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Protein Serine-Threonine Kinases / physiology
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Snail Family Transcription Factors
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism*
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Tumor Suppressor Protein p53 / antagonists & inhibitors
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Protein p53 / physiology*
Substances
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Antineoplastic Agents
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Cell Cycle Proteins
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Snail Family Transcription Factors
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TP53 protein, human
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Transcription Factors
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Tumor Suppressor Protein p53
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases