MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function
Articolo
Data di Pubblicazione:
2012
Citazione:
MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function / S. Donzelli, G. Fontemaggi, F. Fazi, S. Di Agostino, F. Padula, F. Biagioni, P. Muti, S. Strano, G. Blandino. - In: CELL DEATH AND DIFFERENTIATION. - ISSN 1350-9047. - 19:6(2012), pp. 1038-1048.
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Chemoresistance; E2F5; MicroRNA-128-2; Mutant p53; NSCLC; P21waf1; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cisplatin; Cyclin-Dependent Kinase Inhibitor p21; Doxorubicin; Drug Resistance, Neoplasm; E2F5 Transcription Factor; Fluorouracil; Humans; Lung Neoplasms; MicroRNAs; Phosphoproteins; Promoter Regions, Genetic; RNA, Messenger; Transcription, Genetic; Tumor Suppressor Protein p53
Elenco autori:
S. Donzelli, G. Fontemaggi, F. Fazi, S. Di Agostino, F. Padula, F. Biagioni, P. Muti, S. Strano, G. Blandino
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