Intrinsic ubiquitination activity of PCAF controls the stability of the oncoprotein Hdm2

Linares, Laëtitia K.; Kiernan, Rosemary; Triboulet, Robinson; Chable‐Bessia, Christine; Latreille, Daniel; Cuvier, Olivier; Lacroix, Matthieu; Cam, Laurent Le; Coux, Olivier; Benkirane, Monsef

doi:10.1038/ncb1545

Cited by 161 publications

(158 citation statements)

References 27 publications

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“…1 A and B). p300 siRNA has been reported to increase p53 abundance but the mechanism was not determined further (21). p300 and CBP siRNAs both caused increases in steady-state p53 abundance ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Based on findings with the A20, Rabex-5, and E4F1 proteins (10,17,31), a generic Zn 2ϩ -binding region (cys-or cys-his-rich) can encode an active E3, with no clear sequence or structural homology to the Zn 2ϩ -binding RING E3 domain. Perhaps more directly relevant, the evolutionarily related HAT P/CAF was recently shown to encode a noncanonical E3 that targets MDM2 (21). In this case, the protein domain responsible for the activity contains no structural motifs found in known E3 proteins (21).…”

Section: Resultsmentioning

confidence: 99%

“…Perhaps more directly relevant, the evolutionarily related HAT P/CAF was recently shown to encode a noncanonical E3 that targets MDM2 (21). In this case, the protein domain responsible for the activity contains no structural motifs found in known E3 proteins (21).…”

Section: Resultsmentioning

confidence: 99%

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CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53

Shi¹,

Pop²,

Kulikov³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

145

122

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p300 and CREB-binding protein (CBP) act as multifunctional regulators of p53 via acetylase and polyubiquitin ligase (E4) activities. Prior work in vitro has shown that the N-terminal 595 aa of p300 encode both generic ubiquitin ligase (E3) and p53-directed E4 functions. Analysis of p300 or CBP-deficient cells revealed that both coactivators were required for endogenous p53 polyubiquitination and the normally rapid turnover of p53 in unstressed cells. Unexpectedly, p300/CBP ubiquitin ligase activities were absent in nuclear extracts and exclusively cytoplasmic. Consistent with the cytoplasmic localization of its E3/E4 activity, CBP deficiency specifically stabilized cytoplasmic, but not nuclear p53. The N-terminal 616 aa of CBP, which includes the conserved Zn(2+)-binding C/H1-TAZ1 domain, was the minimal domain sufficient to destabilize p53 in vivo, and it included within an intrinsic E3 autoubiquitination activity and, in a two-step E4 assay, exhibited robust E4 activity for p53. Cytoplasmic compartmentalization of p300/CBP\u27s ubiquitination function reconciles seemingly opposed functions and explains how a futile cycle is avoided-cytoplasmic p300/CBP E4 activities ubiquitinate and destabilize p53, while physically separate nuclear p300/CBP activities, such as p53 acetylation, activate p53

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53

Shi¹,

Pop²,

Kulikov³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

145

122

View full text Add to dashboard Cite

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“…Consistently, it was recently reported that the histone acetyl transferase p300-CBP-associated factor ubiquitinates Mdm2, resulting in its proteasomal degradation. 27 At high levels of expression, however, Mdm2 directs its own ubiquitination and subsequent proteasomal degradation. One possible explanation for this concentration dependence is that self-ubiquitination of Mdm2 may occur in trans, which requires the generation of a large enough concentration of Mdm2 homodimers.…”

Section: Degradation Of Ligases Via Self-catalyzed Ubiquitinationmentioning

confidence: 99%

Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms

2011

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Ubiquitin modification of many cellular proteins targets them for proteasomal degradation, but in addition can also serve non-proteolytic functions. Over the last years, a significant progress has been made in our understanding of how modification of the substrates of the ubiquitin system is regulated. However, little is known on how the ubiquitin system that is comprised of B1500 components is regulated. Here, we discuss how the biggest subfamily within the system, that of the E3 ubiquitin ligases that endow the system with its high specificity towards the numerous substrates, is regulated and in particular via self-regulation mediated by ubiquitin modification. Ligases can be targeted for degradation in a self-catalyzed manner, or through modification mediated by an external ligase(s). In addition, non-proteolytic functions of self-ubiquitination, for example activation of the ligase, of E3s are discussed. Cell Death and Differentiation (2011) 18, 1393-1402 doi:10.1038/cdd.2011; published online 4 March 2011One of the major roles of the covalent modification of cellular proteins by ubiquitin is signaling them for proteasomal degradation ( Figure 1). The first step of the modification is catalyzed by the ubiquitin-activating enzyme, E1, which generates a high-energy thiol ester intermediate that is subsequently transferred to the second enzyme, a ubiquitinconjugating enzyme, E2. The third step ascertains substrate specificity, and is catalyzed by one of the numerous (B650) ubiquitin ligases, E3s. Typically, it results in the formation of an isopeptide bond between the C-terminal Gly of ubiquitin and an e-NH 2 group of an internal Lys of the substrate. Less frequently, it can generate a linear peptide bond with the a-NH 2 group, a thiol ester bond with an internal Cys, or an ester bond with a Thr or Ser. The three-step cascade of reactions is repeated, where additional ubiquitin moieties are attached sequentially to one another in an isopeptide bond involving one of the seven internal Lys residues in the ubiquitin moiety, thus generating a polyubiquitin chain. Lys48-based chains serve as a signal for proteasomal degradation, whereas chains based on other internal Lys residues, or modification by single moiety(ies) can serve non-proteolytic functions.Ligases fall into two main families: RING (really interesting new gene) and HECT (homologous to the E6-AP carboxy terminus) domain-containing E3s. RING ligases serve as scaffolds that facilitate direct transfer of ubiquitin from the E2 to the target protein. HECT E3s contain an active Cys residue to which ubiquitin binds prior to its transfer to the substrate (Figure 1). There are B600 RING finger and B30 HECT ligases in humans. Smaller families of ligases (U-box, plant homology domain, and zinc finger) have also been described.An important problem relates to regulation of the ubiquitin system components, and in particular to that of the ligases that are the specific substrate-recognizing elements. 1,2 Phosphorylation of an E3 can activate the protein, such as the ca...

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“…95 Mdm2 steady-state levels observed in mice in which the RING E3 ubiquitin ligase activity of Mdm2 was abrogated by a single-point mutation were comparable with the levels in wild-type mice, implying that Mdm2 stability is controlled by another E3 ubiquitin ligase in vivo. The histone acetyltransferase PCAF (p300-CBP-associated factor) has recently been proposed as a putative candidate 96 as knockdown of PCAF in U2OS and HeLa cancer cell lines stabilized Mdm2. PCAF possesses an intrinsic ubiquitylation activity that is critical for controlling Mdm2 stability, and thus p53 function.…”

Section: Regulation Of Mdm2-mediated P53 Ubiquitylationmentioning

confidence: 99%

Mdm2-mediated ubiquitylation: p53 and beyond

2009

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The really interesting genes (RING)-finger-containing oncoprotein, Mdm2, is a promising drug target for cancer therapy. A key Mdm2 function is to promote ubiquitylation and proteasomal-dependent degradation of the tumor suppressor protein p53. Recent reports provide novel important insights into Mdm2-mediated regulation of p53 and how the physical and functional interactions between these two proteins are regulated. Moreover, a p53-independent role of Mdm2 has recently been confirmed by genetic data. These advances and their potential implications for the development of new cancer therapeutic strategies form the focus of this review.

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Intrinsic ubiquitination activity of PCAF controls the stability of the oncoprotein Hdm2

Cited by 161 publications

References 27 publications

CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53

CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53

Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms

Mdm2-mediated ubiquitylation: p53 and beyond

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