FBXO11 promotes the Neddylation of p53 and inhibits its transcriptional activity.
The p53 tumor suppressor is regulated by post-translational modification, including ubiquitination, phosphorylation and acetylation. It has previously been shown that the ubiquitin ligase Mdm2 also promotes the conjugation of Nedd8, a ubiquitin-like protein, to p53, inhibiting its transcriptional activity. We report the identification of FBXO11, a member of the F-box protein family and a component of the Skp1.Cullin1.F-box (SCF) complex, as a new p53-interacting protein. We show that FBXO11 promotes the neddylation of p53 both in vitro and in vivo. In addition to the C-terminal lysine residues, FBXO11 can also promote Nedd8 conjugation to Lys-320 and Lys-321, and neddylation of p53 leads to suppression of p53 function. This is consistent with recent studies showing that a lysine to arginine mutation at Lys-320 significantly enhances p53 function, although Lys-320 was originally identified as an acetylation site involving PCAF-mediated activation of p53. Our study provides an example of an F-box protein acting as an adaptor protein that can mediate the neddylation of a non-cullin substrate.
Abida
Wassim M
WM
Institute for Cancer Genetics and the Department of Pathology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
Nikolaev
Anatoly
A
Zhao
Wenhui
W
Zhang
Wenzhu
W
Gu
Wei
W
D017209:Apoptosis; D001120:Arginine / Q000737:chemistry; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism; D044842:Cullin Proteins / Q000737:chemistry; D044783:F-Box Proteins / Q000378:metabolism*; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000737:chemistry; D000075687:NEDD8 Protein; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000737:chemistry; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025801:Ubiquitin / Q000737:chemistry; D014452:Ubiquitins / Q000378:metabolism*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D001120:Arginine; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D044783:F-Box Proteins; D051548:Histone Acetyltransferases; D008239:Lysine; D000075687:NEDD8 Protein; D011484:Protein-Arginine N-Methyltransferases; D044843:SKP Cullin F-Box Protein Ligases; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D014452:Ubiquitins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C100318:Cullin 1; C082860:NEDD8 protein, human; C495901:TP53 protein, human; C457579:FBXO11 protein, human