Abstract
The transcription factor p73, a member of the p53 family, mediates cell-cycle arrest and apoptosis in response to DNA damage-induced cellular stress, acting thus as a proapoptotic gene. Similar to p53, p73 activity is regulated by post-translational modification, including phosphorylation, acetylation and ubiquitylation. In C. elegans, the F-box protein FSN-1 controls germline apoptosis by regulating CEP-1, the single ancestral p53 family member. Here we report that FBXO45, the human ortholog of FSN-1, binds specifically to p73 triggering its proteasome-dependent degradation. Importantly, SCFFBXO45 ubiquitylates p73 both in vivo and in vitro. Moreover, siRNA-mediated depletion of FBXO45 stabilizes p73 and concomitantly induces cell death in a p53-independent manner. All together, these results show that the orphan F-box protein FBXO45 regulates the stability of p73, highlighting a conserved pathway evolved from nematode to human by which the p53 members are regulated by an SCF-dependent mechanism.
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Acknowledgements
We thank V De Laurenzi for critically reading the manuscript. This study has been supported by the Medical Research Council, UK; grants from EU EPISTEM (LSHB-CT-019067), ‘Alleanza contro il Cancro’ (ACC12), MIUR/PRIN (RBIP06LCA9_0023), AIRC (2008-20105471), ISS ‘Program Italia-USA’ N526D5, Italian Human ProteomeNet RBRN07BMCT_007 and Telethon (GGPO4110) to GM; and grants from the National Institutes of Health (R01-GM57587, R37-CA76584 and R21-CA125173) and Multiple Myeloma Research Fundation to MP. Research described in this article was also supported in part by Philip Morris USA Inc. and Philip Morris International to GM. MP is an Investigator with the Howard Hughes Medical Institute.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
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Peschiaroli, A., Scialpi, F., Bernassola, F. et al. The F-box protein FBXO45 promotes the proteasome-dependent degradation of p73. Oncogene 28, 3157–3166 (2009). https://doi.org/10.1038/onc.2009.177
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DOI: https://doi.org/10.1038/onc.2009.177
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