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Nucleic Acids Research Advance Access published online on June 25, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn394
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

p73{alpha} isoforms drive opposite transcriptional and post-transcriptional regulation of MYCN expression in neuroblastoma cells

Emilie Horvilleur1, Matthieu Bauer1, David Goldschneider1,2, Xénia Mergui1, Alix de La Motte1, Jean Bénard1,3, Sétha Douc-Rasy1,* and David Cappellen1

1Interactions Molécularies et Cancer, Unité Mixte de Recherche 8126 - Centre National de Recherche Scientifique-Université Paris Sud-11 - Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France, 2Apoptose, Cancer et Développement,Unité Mixte de Recherche 5238, Centre National de Recherche Scientifique - Université de Lyon, Centre Léon Bérard, 69008 Lyon and 3Département de Biologie et Pathologie Médicales, Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France

*To whom correspondence should be addressed. Tel: +33 1 42 11 48 53; Fax: +33 1 42 11 54 94; Email: sdouc{at}igr.fr Correspondence may also be addressed to David Cappellen. Tel: +33 1 42 11 61 44; Fax: +33 1 42 11 54 94; Email: cappellen{at}igr.fr

Received February 15, 2008. Revised June 3, 2008. Accepted June 5, 2008.

MYCN activation, mainly by gene amplification, is one of the most frequent molecular events in neuroblastoma (NB) oncogenesis, and is associated with increased malignancy and decreased neuronal differentiation propensity. The frequency of concomitant loss of heterozygosity at the 1p36.3 locus, which harbours the p53 anti-oncogene homologue TP73, indicates that MYCN and p73 alterations may cooperate in the pathogenesis of NB. We have previously shown that p73 isoforms are deregulated in NB tumours and that TAp73 co-operates synergistically with p53 for apoptosis of NB cells, whereas {Delta}Np73 activates the expression of neuronal differentiation genes such as BTG2. Herein, using both ectopic expression and RNA interference-mediated silencing of p73 in MYCN amplified NB cells, we show that p73{alpha} isoforms inhibit MYCN expression at both transcript and protein levels, in spite of transactivator effects on MYCN promoter. To explain this paradox, we found that TAp73{alpha} exerts negative post-transcriptional effects leading to reduced MYCN mRNA stability. RNA immunoprecipitation experiments suggest that this dominant inhibitory post-transcriptional effect could be due to an interaction between the p73 protein and MYCN mRNA, a hypothesis also raised for the regulation of certain genes by the p53 protein.


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