Blocking of p53-Snail binding, promoted by oncogenic K-Ras, recovers p53 expression and function.
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.
Lee
Sun-Hye
SH
Department of Molecular Biology, College of Natural Science, Pusan National University, Geumjeong-gu, Busan, South Korea.
Lee
Su-Jin
SJ
Jung
Yeon Sang
YS
Xu
Yongbin
Y
Kang
Ho Sung
HS
Ha
Nam-Chul
NC
Park
Bum-Joon
BJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D000071250:Snail Family Transcription Factors; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases