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

Fingerprint

MicroRNAs
Non-Small Cell Lung Carcinoma
Mutant Proteins
Caspase 3
Doxorubicin
Cisplatin
Lung Neoplasms
Apoptosis
Messenger RNA
Mutation
Genes
Neoplasms
Proteins

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 journalArticle

Donzelli, S, Fontemaggi, G, Fazi, F, Di Agostino, S, Padula, F, Biagioni, F, Muti, P, Strano, S & Blandino, G 2012, 'MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function', Cell Death and Differentiation, vol. 19, no. 6, pp. 1038-1048. https://doi.org/10.1038/cdd.2011.190
Donzelli, S. ; Fontemaggi, G. ; Fazi, F. ; Di Agostino, S. ; Padula, F. ; Biagioni, F. ; Muti, P. ; Strano, S. ; Blandino, G. / MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function. In: Cell Death and Differentiation. 2012 ; Vol. 19, No. 6. pp. 1038-1048.
@article{8b6dd373b225489795b44280d67debec,
title = "MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function",
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.",
keywords = "Chemoresistance, E2F5, MicroRNA-128-2, Mutant p53, NSCLC, P21waf1",
author = "S. Donzelli and G. Fontemaggi and F. Fazi and {Di Agostino}, S. and F. Padula and F. Biagioni and P. Muti and S. Strano and G. Blandino",
year = "2012",
month = "6",
doi = "10.1038/cdd.2011.190",
language = "English",
volume = "19",
pages = "1038--1048",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Nature Publishing Group",
number = "6",

}

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 -