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 language | English |
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Pages (from-to) | 1038-1048 |
Number of pages | 11 |
Journal | Cell Death and Differentiation |
Volume | 19 |
Issue number | 6 |
DOIs | |
Publication status | Published - Jun 2012 |
Keywords
- Chemoresistance
- E2F5
- MicroRNA-128-2
- Mutant p53
- NSCLC
- P21waf1
ASJC Scopus subject areas
- Cell Biology
- Molecular Biology