title: MDM4 regulation by the let-7 miRNA family in the DNA damage response of glioma cells.
abstract: Despite extensive investigation into the role of let-7 miRNAs in pathological tumor processes, their involvement in the DNA damage response remains unclear. Here we show that most let-7 family members down-regulate MDM4 expression via binding to MDM4 mRNA at a conserved DNA sequence. Expression of exogenous let-7 miRNA mimics decreased MDM4 protein but not mRNA levels. Several DNA damage reagents increased let-7 expression, thereby decreasing MDM4 protein levels in glioma cells. Inhibition of endogenous let-7 with antisense RNAs rescued MDM4 protein levels with or without MG132, a proteasome-dependent degradation inhibitor. An MDM4 mutation identified in a glioma patient was associated with loss of the putative MDM4 target site. Therefore, let-7 binding to MDM4 is implicated in the DNA damage response.
authors.affiliation: State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China; Shenzhen Weiguang Biological Products Co., Ltd., Shenzhen 518107, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Gynecology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China; Gene Science & Health Company, Shenzhen 518048, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Mengdie
authors.initials: M
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Qiuxian
authors.initials: Q
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: jiangssh@mail.sysu.edu.cn.
authors.forename: Songshan
authors.initials: S
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C487931:mirnlet7 microRNA, human
keywords: Coding DNA sequence; DNA damage; Glioma; MDM4; MicroRNA let-7