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First published online 1 March 2005
doi: 10.1242/jcs.01704

Journal of Cell Science 118, 1245-1253 (2005)
Published by The Company of Biologists 2005
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Research Article

The neurogene BTG2TIS21/PC3 is transactivated by {Delta}Np73{alpha} via p53 specifically in neuroblastoma cells

David Goldschneider1, Karine Million1, Anne Meiller3, Hedi Haddada1, Alain Puisieux2, Jean Bénard1, Evelyne May3,* and Sétha Douc-Rasy1,{ddagger}

1 CNRS UMR 8126, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94800 Villejuif, France
2 INSERM U590, Centre Leon Bérard, 28 rue Laënnec, 69008 Lyon, France
3 CEA-CNRS UMR217, PB6, 92265 Fontenay-aux-Roses, France

{ddagger} Author for correspondence (e-mail: sdouc{at}igr.fr)

Accepted 6 January 2005

The p53 gene and its homologue p73 are rarely mutated in neuroblastoma. In recent studies, we showed that overexpression of {Delta}Np73{alpha}, an isoform lacking the N-terminal transactivation (TA) domain, surprisingly induces p53 protein accumulation in the wild-type (wt) p53 human neuroblastoma line SH-SY5Y. As can be expected owing to its dominant-negative effect, {Delta}Np73{alpha} inhibits Waf1/p21 gene expression, but equally importantly, it upregulates BTG2TIS21/PC3, another p53 target gene. This effect is not observed in neuroblastoma cells that express a mutated p53. To better understand the {Delta}Np73-mediated transactivation of the BTG2TIS21/PC3 gene we performed luciferase assays with two reporter plasmids harboring long and short BTG2 promoter sequences in three human neuroblastoma cell lines and one breast cancer cell line. Our results demonstrate that BTG2TIS21/PC3 transactivation by {Delta}Np73{alpha} depends on both p53 status (as it is not observed in a p53–/– neuroblastoma cell line) and cellular context (as it occurs in a p53+/+ neuroblastoma cell line but not in a p53+/+ breast tumor cell line). The fact that {Delta}Np73{alpha} may either inhibit or stimulate wt-p53 transcriptional activity, depending on both the p53 target gene and the cellular context, was confirmed by real-time quantitative PCR. Moreover, transactivation of the BTG2TIS21/PC3 promoter requires a complete {Delta}Np73{alpha} C-terminus sequence as it is not observed with {Delta}Np73ß, which lacks most of the C-terminal domain. We have previously shown that {Delta}Np73{alpha} is the only p73 isoform expressed in undifferentiated neuroblastoma tumors. In light of all these findings, we propose that {Delta}Np73{alpha} not only acts as an inhibitor of p53/TAp73 functions in neuroblastoma tumors, but also cooperates with wt-p53 in playing a physiological role through the activation of BTG2TIS21/PC3 gene expression.

Key words: p73, p53, BTG2TIS21/PC3, Transactivation, Neuroblastoma, Apoptosis, Differentiation, Development


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