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  • Original Paper
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TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activity

Abstract

TP53INP1 is an alternatively spliced gene encoding two nuclear protein isoforms (TP53INP1α and TP53INP1β), whose transcription is activated by p53. When overexpressed, both isoforms induce cell cycle arrest in G1 and enhance p53-mediated apoptosis. TP53INP1s also interact with the p53 gene and regulate p53 transcriptional activity. We report here that TP53INP1 expression is induced during experimental acute pancreatitis in p53−/− mice and in cisplatin-treated p53−/− mouse embryo fibroblasts (MEFs). We demonstrate that ectopic expression of p73, a p53 homologue, leads to TP53INP1 induction in p53-deficient cells. In turn, TP53INP1s alters the transactivation capacity of p73 on several p53-target genes, including TP53INP1 itself, demonstrating a functional association between p73 and TP53INP1s. Also, when overexpressed in p53-deficient cells, TP53INP1s inhibit cell growth and promote cell death as assessed by cell cycle analysis and colony formation assays. Finally, we show that TP53INP1s potentiate the capacity of p73 to inhibit cell growth, that effect being prevented when the p53 mutant R175H is expressed or when p73 expression is blocked by a siRNA. These results suggest that TP53INP1s are functionally associated with p73 to regulate cell cycle progression and apoptosis, independently from p53.

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Acknowledgements

We thank Drs S Vasseur and P Soubeyran for helpful comments, V Fontaine for her help in Western blots and monoclonal antibody characterizations, A Giovannetti for siRNA and FACS analysis, R Grimaud and P Berthézène for technical help. We are grateful to G Blandino and S Das for providing us with expression plasmids (pcDNA-p73α-HA and pcDNA-p53R175H) and adenovirus (Ad-p73β), respectively. This work was supported by grants from INSERM R Tomasini is supported by a fellowship from the Ministère de la Recherche et de la Technologie, and J Nowak is supported by a fellowship from the Région Provence-Alpes-Côte-d’Azur and INSERM.

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Correspondence to Nelson J Dusetti.

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Tomasini, R., Seux, M., Nowak, J. et al. TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activity. Oncogene 24, 8093–8104 (2005). https://doi.org/10.1038/sj.onc.1208951

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