title: MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function.
abstract: p53 mutations have profound effects on non-small-cell lung cancer (NSCLC) resistance to chemotherapeutic treatments. Mutant p53 proteins are usually expressed at high levels in tumors, where they exert oncogenic functions. Here we show that p53R175H, a hotspot p53 mutant, induces microRNA (miRNA)-128-2 expression. Mutant p53 binds to the putative promoter of miR128-2 host gene, ARPP21, determining a concomitant induction of ARPP21 mRNA and miR-128-2. miR-128-2 expression in lung cancer cells inhibits apoptosis and confers increased resistance to cisplatin, doxorubicin and 5-fluorouracyl treatments. At the molecular level, miR-128-2 post-transcriptionally targets E2F5 and leads to the abrogation of its repressive activity on p21(waf1) transcription. p21(waf1) protein localizes to the cytoplasmic compartment, where it exerts an anti-apoptotic effect by preventing pro-caspase-3 cleavage. This study emphasizes miRNA-128-2 role as a master regulator in NSCLC chemoresistance.
authors.affiliation: Translational Oncogenomics Unit, National Cancer Institute Regina Elena Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Donzelli
authors.forename: G
authors.initials: G
authors.lastname: Fontemaggi
authors.forename: F
authors.initials: F
authors.lastname: Fazi
authors.forename: S
authors.initials: S
authors.lastname: Di Agostino
authors.forename: F
authors.initials: F
authors.lastname: Padula
authors.forename: F
authors.initials: F
authors.lastname: Biagioni
authors.forename: P
authors.initials: P
authors.lastname: Muti
authors.forename: S
authors.initials: S
authors.lastname: Strano
authors.forename: G
authors.initials: G
authors.lastname: Blandino
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D050700:E2F5 Transcription Factor / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D050700:E2F5 Transcription Factor; C545189:MIRN128 microRNA, human; D035683:MicroRNAs; D010750:Phosphoproteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C061368:cyclic AMP-regulated phosphoprotein ARPP-21; D004317:Doxorubicin; D002945:Cisplatin; D005472:Fluorouracil