title: miR-605 joins p53 network to form a p53:miR-605:Mdm2 positive feedback loop in response to stress.
abstract: In cancers with wild-type (WT) p53 status, the function of p53 is inhibited through direct interaction with Mdm2 oncoprotein, a negative feedback loop to limit the function of p53. In response to cellular stress, p53 escapes the p53:Mdm2 negative feedback to accumulate rapidly to induce cell cycle arrest and apoptosis. We demonstrate herein that an microRNA miR-605 is a new component in the p53 gene network, being transcriptionally activated by p53 and post-transcriptionally repressing Mdm2. Activation of p53 upregulated miR-605 via interacting with the promoter region of the gene. Overexpression of miR-605 directly decreased Mdm2 expression at the post-transcriptional level but indirectly increased the transcriptional activity of p53 on miR-34a via downregulating Mdm2; knockdown of miR-605 did the opposite. Mdm2 inhibitor upregulated expression of both miR-34a and miR-605, which was mitigated by p53 inhibitor. miR-605 preferentially induced apoptosis in WT p53-expressing cells, an effect abolished by p53 inhibition. These results indicate that miR-605 acts to interrupt p53:Mdm2 interaction to create a positive feedback loop aiding rapid accumulation of p53 to facilitate its function in response to stress.
authors.affiliation: Research Center, Montreal Heart Institute, Montreal, Canada.
authors.forename: Jiening
authors.initials: J
authors.lastname: Xiao
authors.forename: Huixian
authors.initials: H
authors.lastname: Lin
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Luo
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Luo
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D025461:Feedback, Physiological / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008156:Luciferases; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C556602:MIRN605 microRNA, human; D035683:MicroRNAs; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569718:PRKG1 protein, human; D053148:Caspase 3; C022616:thiazolyl blue