E4F1 is an atypical ubiquitin ligase that modulates p53 effector functions independently of degradation.
p53 is regulated by multiple posttranslational modifications, including Hdm2-mediated ubiquitylation that drives its proteasomal degradation. Here, we identify the p53-associated factor E4F1, a ubiquitously expressed zinc-finger protein first identified as a cellular target of the viral oncoprotein E1A, as an atypical ubiquitin E3 ligase for p53 that modulates its effector functions without promoting proteolysis. E4F1 stimulates oligo-ubiquitylation in the hinge region of p53 on lysine residues distinct from those targeted by Hdm2 and previously described to be acetylated by the acetyltransferase PCAF. E4F1 and PCAF mediate mutually exclusive posttranslational modifications of p53. E4F1-dependent Ub-p53 conjugates are associated with chromatin, and their stimulation coincides with the induction of a p53-dependent transcriptional program specifically involved in cell cycle arrest, and not apoptosis. Collectively, our data reveal that E4F1 is a key posttranslational regulator of p53, which modulates its effector functions involved in alternative cell fates: growth arrest or apoptosis.
Le Cam
Laurent
L
Institut de Génétique Moléculaire CNRS-UMII UMR5535, IFR122, Montpellier 34293, France. llecam@igmm.cnrs.fr
Linares
Laëtitia K
LK
Paul
Conception
C
Julien
Eric
E
Lacroix
Matthieu
M
Hatchi
Elodie
E
Triboulet
Robinson
R
Bossis
Guillaume
G
Shmueli
Ayelet
A
Rodriguez
Manuel S
MS
Coux
Olivier
O
Sardet
Claude
C
D000107:Acetylation / Q000528:radiation effects; D021581:Active Transport, Cell Nucleus / Q000528:radiation effects; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000528:radiation effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014466:Ultraviolet Rays; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D018797:Cell Cycle Proteins; D002843:Chromatin; D051548:Histone Acetyltransferases; D008239:Lysine; D051736:Proto-Oncogene Proteins c-mdm2; D012097:Repressor Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C513814:E4F1 protein, human; C497206:MDM2 protein, human