The F-box protein FBXO45 promotes the proteasome-dependent degradation of p73.

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, SCF(FBXO45) 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.
Mesh Terms:
Animals, Breast Neoplasms, CHO Cells, Cell Death, Cell Line, Cell Line, Transformed, Cell Line, Tumor, Cricetinae, Cricetulus, DNA-Binding Proteins, F-Box Proteins, Green Fluorescent Proteins, Hela Cells, Hemagglutinins, Humans, Kidney, Leupeptins, Mutation, Neuroblastoma, Nuclear Proteins, Proteasome Endopeptidase Complex, Protein Binding, RNA, Small Interfering, Substrate Specificity, Temperature, Transfection, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination
Oncogene
Date: Sep. 03, 2009
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