Abstract
Inactivation of the tumour suppressor p53 is the most common defect in cancer cells. p53 is a sequence specific transcription factor that is activated in response to various forms of genotoxic stress to induce cell cycle arrest and apoptosis. Induction of p53 is subjected to complex and strict control through several pathways, as it will often determine cellular fate. The p73 protein shares strong structural and functional similarities with p53 such as the potential to activate p53 responsive genes and the ability to induce apoptosis. In addition to alternative splicing at the carboxyl terminus which yields several p73 isoforms, a p73 variant lacking the N-terminal transactivation domain (ΔNp73) was described in mice. In this study, we report the cloning and characterisation of the human ΔNp73 isoforms, their regulation by p53 and their possible role in carcinogenesis. As in mice, human ΔNp73 lacks the transactivation domain and starts with an alternative exon (exon 3′). Its expression is driven by a second promoter located in a genomic region upstream of this exon, supporting the idea of two independently regulated proteins, derived from the same gene. As anticipated, ΔNp73 is capable of regulating TAp73 and p53 function since it is able to block their transactivation activity and their ability to induce apoptosis. Interestingly, expression of the ΔNp73 is strongly up-regulated by the TA isoforms and by p53, thus creating a feedback loop that tightly regulates the function of TAp73 and more importantly of p53. The regulation of ΔNp73 is exerted through a p53 responsive element located on the ΔN promoter. Expression of ΔNp73 not only regulates the function of p53 and TAp73 but also shuts off its own expression, once again finely regulating the whole system. Our data also suggest that increased expression of ΔNp73, functionally inactivating p53, could be involved in tumorogenesis. An extensive analysis of the expression pattern of ΔNp73 in primary tumours would clarify this issue.
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Abbreviations
- ΔN:
-
amino-terminus deleted
- TA:
-
transactivation
- DBD:
-
DNA-binding domain
- OD:
-
oligomerisation domain
- DMEM:
-
Dulbecco's Modified essential Medium
- PI:
-
propidium iodide
- GFP:
-
green fluorescent protein
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Acknowledgements
The HaCaT cell line was a kind gift from N. Fusenig (Heidelberg, Germany). We would like to thank Dr. R. Kalejta and Dr. A.J. Beavis for the GFP-spectrin expression vector. This work was supported by grants from the Swiss National Foundation (3200-053596.98), from the Swiss Cancer League (KFS 156-9-1995) and the Ursula-Hecht-Stiftung. Telethon grant E872, AIRC, MURST and EU grant QLGI-1999-00739 to G Melino. Telethon grant E1224 to V De Laurenzi.
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Grob, T., Novak, U., Maisse, C. et al. Human ΔNp73 regulates a dominant negative feedback loop for TAp73 and p53. Cell Death Differ 8, 1213–1223 (2001). https://doi.org/10.1038/sj.cdd.4400962
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DOI: https://doi.org/10.1038/sj.cdd.4400962
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