Abstract
The discovery of the p73 and p63 genes, homologous to p53 tumor suppressor has uncovered a family of transcription factors and widened the scenario of cell cycle control and apoptosis. We have identified a putative p53-responsive element in the human adenosine deaminase (ADA) gene, an important enzyme involved in nucleotide metabolism, the deficit of which causes the inhibition of DNA synthesis and repair. Here, we demonstrate that the ectopic expression of p73 isoforms leads to the ADA gene upregulation, showing for the first time a correlation between p73 and ADA. We found that p73 promotes ADA gene expression following a dNTP unbalance generated by ADA enzyme deficiency and 2′deoxyadenosine accumulation. The abrogation of p73 transcriptional activity by the specific dominant-negative p73DD abolishes ADA induction. By contrast, the ADA gene does not appear to be a functional p53 target in the physiological conditions we tested. On the whole, our results contribute to the emerging picture that p73 could play a different role from p53 in normal growth and development by inducing alternative target genes, which are not shared by p53.
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Acknowledgements
The A2780/pcDNA3 and A2780/p73α.4 clones cell lines were kindly provided by Dr Massimo Broggini of the ‘Mario Negri’ Institute, Milan. The H1299-p53-tet cell line was kindly provided by Professor David Lane of the University of Dundee. The recombinant plasmids pcDNA3 p73α and p73β were kindly provided by Dr G Melino of the IDI-IRCCS Biochemistry Lab., c/o University Tor Vergata, Rome. We wish to thank Dr Vincenzo De Salvo and Dr Fortunato Morabito of the Centro Trapianti Midollo Osseo e Terapie Emato-Oncologiche Sovramassimali ‘Alberto Neri’ (Reggio Calabria) for providing 2′-deoxycoformycin (dCF). We wish to thank Dr Farizio Loiacono, Dr Konstantinos Lefkimmiatis and Dr Rosalia Marzella for their help. We wish to acknowledge Dr Aurelio Reyes and D'Erchia Anna Maria for critical discussion. This work was supported by grants from the Italian Association for Cancer Research (AIRC) and by MURST Ingegneria Molecolare Cluster C03 Legge 488/92. MG was supported by a fellowship from the Italian Foundation for Cancer Research (FIRC).
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Tullo, A., Mastropasqua, G., Bourdon, J. et al. Adenosine deaminase, a key enzyme in DNA precursors control, is a new p73 target. Oncogene 22, 8738–8748 (2003). https://doi.org/10.1038/sj.onc.1206967
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DOI: https://doi.org/10.1038/sj.onc.1206967