Abstract
Regulation of the p73 gene is complex due to the presence of two promoters and the very complex mRNA maturation in both the N-terminal and C-terminal parts of the protein. We have found an additional regulation mechanism for the p73-α form that occurs through proteolytic cleavage connected to the activity of the serine protease HtrA2. Following apoptotic stimuli, HtrA2 accumulates in the nucleus and cleaves p73α in the C-terminal portion, enabling the protein to increase its transactivation activity on the apoptotic gene bax but not on the cell-cycle regulator gene p21. In the presence of HtrA2, p73 is more prone to cause caspase activation and nuclei fragmentation: p73 needs HtrA2 to activate and enhance its apoptotic functions. This new relation between p73 and HtrA2 may help to understand the different behavior of the p73 protein in cell physiology and in the responses of cancer cells to chemotherapy.
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Abbreviations
- TA:
-
transactivation proficient
- DN:
-
N-terminus deficient
- HtrA2:
-
high temperature requirement A
- MEF:
-
mouse embryonic fibroblast
- P1:
-
TA promoter
- P2:
-
DN promoter
- doxo:
-
doxorubicin
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Acknowledgements
We thank V Fedele for special advices on HtrA2 experiments. We thank V De Laurenzi, G Melino, K Sabapathy and LM Martins for reagents. JD Baggott kindly revised the paper. The generous contribution of the Italian Association for Cancer Research is gratefully acknowledged. This work was partially supported by grants from the Italian Ministry of Health, Fondazione CARIPLO and Negri-Weizmann to MB. FV is a visiting scientist from the Institute of Cytology, Russian Academy of Science, St Petersburg, Russia.
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Marabese, M., Mazzoletti, M., Vikhanskaya, F. et al. HtrA2 enhances the apoptotic functions of p73 on bax. Cell Death Differ 15, 849–858 (2008). https://doi.org/10.1038/cdd.2008.7
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DOI: https://doi.org/10.1038/cdd.2008.7
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