Abstract
The p53 tumor suppressor gene is activated in response to DNA damage resulting in either growth arrest or apoptosis. We previously demonstrated the specific involvement of homeodomain interacting protein-kinase 2 (HIPK2), a nuclear serine/threonine kinase, in inducing p53-dependent apoptosis through selective p53 phosphorylation at serine 46 after severe genotoxic damage. Here we show that HIPK2 contributes to p53 regulation, independently from serine 46 phosphorylation upon nonapoptotic DNA damage such as that induced by cytostatic doses of cisplatin. We show that HIPK2 depletion by RNA interference inhibits p53 binding to the p21Waf1 promoter affecting its p53-induced transactivation thereby allowing cell proliferation. We found that nonapoptotic DNA damage induces p53 acetylation mediated by the HAT protein PCAF and this p53 post-translational modification is abolished by HIPK2 depletion. In this regard, we found that HIPK2 cooperates with PCAF to induce selectively p53 transcriptional activity toward the p21Waf1 promoter while depletion of either HIPK2 or PCAF abolished this function. These data show that HIPK2 regulates the p53 growth arrest function through its PCAF-mediated acetylation.
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Acknowledgements
We thank all the people cited in the text for their generous gifts of reagents. We are particularly grateful to M Levrero, A Damalas, M Fanciulli, and G Blandino for constant availability, scientific support, and critical reading of the manuscript. We also thank G Fontemaggi, A Gurtner, and T Bruno for their expert technical assistance. This work was supported by grants from AIRC, MIUR-Cofin, MURST-Fondi Ateneo, and FIRB-MIUR.
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Di Stefano, V., Soddu, S., Sacchi, A. et al. HIPK2 contributes to PCAF-mediated p53 acetylation and selective transactivation of p21Waf1 after nonapoptotic DNA damage. Oncogene 24, 5431–5442 (2005). https://doi.org/10.1038/sj.onc.1208717
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DOI: https://doi.org/10.1038/sj.onc.1208717
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