Blocking of p53-Snail Binding, Promoted by Oncogenic K-Ras, Recovers p53 Expression and function

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2009-01, Vol.11 (1), p.22,IN1-31,IN6
• Main Authors: Lee, Sun-Hye, Lee, Su-Jin, Jung, Yeon Sang, Xu, Yongbin, Kang, Ho Sung, Ha, Nam-Chul, Park, Bum-Joon
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins - physiology; Cells, Cultured; Down-Regulation - drug effects; Drug Design; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Genes, ras - physiology; HCT116 Cells; Humans; Male; Mice; Models, Biological; Neoplasms - drug therapy; Neoplasms - genetics; Protein Binding - drug effects; Protein Binding - physiology; Protein-Serine-Threonine Kinases - physiology; Snail Family Transcription Factors; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Protein p53 - physiology
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.81006

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.