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. Cell Death and Differentiation (2012) 19, 1038-1048; doi:10.1038/cdd.2011.190; published online 23 December 2011
MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function / S., Donzelli; G., Fontemaggi; Fazi, Francesco; S., Di Agostino; F., Padula; F., Biagioni; P., Muti; S., Strano; G., Blandino. - In: CELL DEATH AND DIFFERENTIATION. - ISSN 1350-9047. - STAMPA. - 19:6(2012), pp. 1038-1048. [10.1038/cdd.2011.190]
MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function
FAZI, Francesco;
2012
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. Cell Death and Differentiation (2012) 19, 1038-1048; doi:10.1038/cdd.2011.190; published online 23 December 2011I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
