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 |
|---|---|
| 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 |
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Keywords
- Chemoresistance
- E2F5
- MicroRNA-128-2
- Mutant p53
- NSCLC
- P21waf1
ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
Cite this
MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function. / Donzelli, S.; Fontemaggi, G.; Fazi, F.; Di Agostino, S.; Padula, F.; Biagioni, F.; Muti, P.; Strano, S.; Blandino, G.
In: Cell Death and Differentiation, Vol. 19, No. 6, 06.2012, p. 1038-1048.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function
AU - Donzelli, S.
AU - Fontemaggi, G.
AU - Fazi, F.
AU - Di Agostino, S.
AU - Padula, F.
AU - Biagioni, F.
AU - Muti, P.
AU - Strano, S.
AU - Blandino, G.
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
KW - Chemoresistance
KW - E2F5
KW - MicroRNA-128-2
KW - Mutant p53
KW - NSCLC
KW - P21waf1
UR - http://www.scopus.com/inward/record.url?scp=84860745157&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84860745157&partnerID=8YFLogxK
U2 - 10.1038/cdd.2011.190
DO - 10.1038/cdd.2011.190
M3 - Article
C2 - 22193543
AN - SCOPUS:84860745157
VL - 19
SP - 1038
EP - 1048
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 6
ER -