A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma.
Chemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MD...
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doaj-1c189849586945f49531493917b116fb2020-11-24T22:03:20ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01811e7984310.1371/journal.pone.0079843A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma.Eveline BarbieriKatleen De PreterMario CapassoPeter JohanssonTsz-Kwong ManZaowen ChenParis StowersGian Paolo ToniniFrank SpelemanJason M ShohetChemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MDM2-p53 interaction are able to overcome this repression and potently activate p53 dependent apoptosis in malignancies with intact p53 downstream signaling. We used the small molecule MDM2 inhibitor, Nutlin-3a, to determine the p53 drug response signature in neuroblastoma cells. In addition to p53 mediated apoptotic signatures, GSEA and pathway analysis identified a set of p53-repressed genes that were reciprocally over-expressed in neuroblastoma patients with the worst overall outcome in multiple clinical cohorts. Multifactorial regression analysis identified a subset of four genes (CHAF1A, RRM2, MCM3, and MCM6) whose expression together strongly predicted overall and event-free survival (p<0.0001). The expression of these four genes was then validated by quantitative PCR in a large independent clinical cohort. Our findings further support the concept that oncogene-driven transcriptional networks opposing p53 activation are essential for the aggressive behavior and poor response to therapy of high-risk neuroblastoma.http://europepmc.org/articles/PMC3865347?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Eveline Barbieri Katleen De Preter Mario Capasso Peter Johansson Tsz-Kwong Man Zaowen Chen Paris Stowers Gian Paolo Tonini Frank Speleman Jason M Shohet |
spellingShingle |
Eveline Barbieri Katleen De Preter Mario Capasso Peter Johansson Tsz-Kwong Man Zaowen Chen Paris Stowers Gian Paolo Tonini Frank Speleman Jason M Shohet A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. PLoS ONE |
author_facet |
Eveline Barbieri Katleen De Preter Mario Capasso Peter Johansson Tsz-Kwong Man Zaowen Chen Paris Stowers Gian Paolo Tonini Frank Speleman Jason M Shohet |
author_sort |
Eveline Barbieri |
title |
A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. |
title_short |
A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. |
title_full |
A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. |
title_fullStr |
A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. |
title_full_unstemmed |
A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. |
title_sort |
p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2013-01-01 |
description |
Chemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MDM2-p53 interaction are able to overcome this repression and potently activate p53 dependent apoptosis in malignancies with intact p53 downstream signaling. We used the small molecule MDM2 inhibitor, Nutlin-3a, to determine the p53 drug response signature in neuroblastoma cells. In addition to p53 mediated apoptotic signatures, GSEA and pathway analysis identified a set of p53-repressed genes that were reciprocally over-expressed in neuroblastoma patients with the worst overall outcome in multiple clinical cohorts. Multifactorial regression analysis identified a subset of four genes (CHAF1A, RRM2, MCM3, and MCM6) whose expression together strongly predicted overall and event-free survival (p<0.0001). The expression of these four genes was then validated by quantitative PCR in a large independent clinical cohort. Our findings further support the concept that oncogene-driven transcriptional networks opposing p53 activation are essential for the aggressive behavior and poor response to therapy of high-risk neuroblastoma. |
url |
http://europepmc.org/articles/PMC3865347?pdf=render |
work_keys_str_mv |
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