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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1038-1048
Number of pages11
JournalCell Death and Differentiation
Volume19
Issue number6
DOIs
Publication statusPublished - Jun 2012

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Keywords

  • Chemoresistance
  • E2F5
  • MicroRNA-128-2
  • Mutant p53
  • NSCLC
  • P21waf1

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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