E4F1 Is an Atypical Ubiquitin Ligase that Modulates p53 Effector Functions Independently of Degradation

Abstract

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.

PJA2 ubiquitinates the HIV-1 Tat protein with atypical chain linkages to activate viral transcription

“…However some recent examples point to positive signaling functions for non-Lys63 linkages3454. Because Tat ubiquitination is non-degradative, we wished to determine the nature of its linkage.…”

“…The tumor suppressor, p53, and proto-oncogene, Myc, are both tightly regulated by numerous ubiquitin ligases that modify multiple lysine residues in each protein. Ubiquitin modification of these transcription factors can lead to proteasomal degradation27282930, protein stabilization3132, or protein re-localization3334. This diversity of functional outputs makes ubiquitination an attractive means to expand the function of a viral protein as it hijacks the host cell machinery, and especially to enhance the role of Tat in regulating transcription.…”

Global analyses of Chromosome 17 and 18 genes of lung telocytes compared with mesenchymal stem cells, fibroblasts, alveolar type II cells, airway epithelial cells, and lymphocytes

“…E4F1 controls mammalian embryonic and somatic cell proliferation and survival, and is a key posttranslational regulator of p53, which modulates its effector functions involved in cell growth arrest or apoptosis [51,52]. The low expression of E4F1 in TCs has a positive effect on cell proliferation and differentiation and maintains the viability and activity of TCs in tissues.…”

MDM2 and MDM4: p53 regulators as targets in anticancer therapy

“…A nonexclusive possibility is that variations in p53 levels may affect its interaction with other proteins proposed to promote cell cycle arrest (e.g. E4F1; LeCam et al, 2006) or apoptosis (e.g. ASPP proteins or TIP60; Sykes et al, 2006;Tang et al, 2006b;Trigiante and Lu, 2006), thereby leading to different responses.…”