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Title: Functional analysis of the p53 pathway in neuroblastoma cells using the small-molecule MDM2 antagonist nutlin-3
Authors: Van Maerken, Tom ×
Rihani, Ali
Dreidax, Daniel
De Clercq, Sarah
Yigit, Nurten
Marine, Chris
Westermann, Frank
De Paepe, Anne
Vandesompele, Jo
Speleman, Frank #
Issue Date: Jun-2011
Publisher: American Association for Cancer Research, Inc.
Series Title: Molecular Cancer Therapeutics vol:10 issue:6 pages:983-993
Abstract: Suppression of p53 activity is essential for proliferation and survival of tumor cells. A direct p53-activating compound, nutlin-3, was used in this study, together with p53 mutation analysis, to characterize p53 pathway defects in a set of 34 human neuroblastoma cell lines. We identified 9 cell lines (26%) with a p53 loss-of-function mutation, including 6 missense mutations, 1 nonsense mutation, 1 in-frame deletion, and 1 homozygous deletion of the 3' end of the p53 gene. Sensitivity to nutlin-3 was highly predictive of absence of p53 mutation. Signaling pathways downstream of p53 were functionally intact in 23 of 25 cell lines with wild-type p53. Knockdown and overexpression experiments revealed a potentiating effect of p14(ARF) expression on the response of neuroblastoma cells to nutlin-3. Our findings shed light on the spectrum of p53 pathway lesions in neuroblastoma cells, indicate that defects in effector molecules downstream of p53 are remarkably rare in neuroblastoma, and identify p14(ARF) as a determinant of the outcome of the response to MDM2 inhibition. These insights may prove useful for the clinical translation of evolving strategies aimed at p53 reactivation and for the development of new therapeutic approaches.
URI: 
ISSN: 1535-7163
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Non-KU Leuven Association publications
× corresponding author
# (joint) last author

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