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.
Peschiaroli
A
A
IDI-IRCCS Biochemistry Laboratory, Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome 00133, Italy.
Scialpi
F
F
Bernassola
F
F
Pagano
M
M
Melino
G
G
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D016466:CHO Cells; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006388:Hemagglutinins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology; D007976:Leupeptins / Q000494:pharmacology; D009154:Mutation; D009447:Neuroblastoma / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D013379:Substrate Specificity; D013696:Temperature; D014162:Transfection; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
D004268:DNA-Binding Proteins; D044783:F-Box Proteins; C503710:FBXO45 protein, human; D006388:Hemagglutinins; D007976:Leupeptins; D009687:Nuclear Proteins; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde