Blocking of p53-Snail Binding, Promoted by Oncogenic K-Ras, Recovers p53 Expression and function
| Autor: | Sun-Hye Lee, Su-Jin Lee, Yeon Sang Jung, Yongbin Xu, Ho Sung Kang, Nam-Chul Ha, Bum-Joon Park |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: | |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 11, Iss 1, Pp 22-31 (2009) |
| Druh dokumentu: | article |
| ISSN: | 1476-5586 1522-8002 |
| DOI: | 10.1593/neo.81006 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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