SnapShot: p53 Posttranslational Modifications

Kruse, Jan-Philipp; Gu, Wei

doi:10.1016/j.cell.2008.05.020

Cited by 141 publications

(117 citation statements)

References 10 publications

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“…This is not a trivial issue because p53 can be posttranslationally modified by several distinct mechanisms at multiple sites and recruit coactivators and corepressors (Kruse and Gu, 2008). A recent study showed that Skp2 sequesters the acetyltransferase p300, from binding p53 (Kitagawa et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Skp2 Regulates G2/M Progression in a p53-dependent Manner

Aplin

2008

MBoC

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Targeted proteasomal degradation mediated by E3 ubiquitin ligases controls cell cycle progression, and alterations in their activities likely contribute to malignant cell proliferation. S phase kinase-associated protein 2 (Skp2) is the F-box component of an E3 ubiquitin ligase complex that targets p27 Kip1 and cyclin E1 to the proteasome. In human melanoma, Skp2 is highly expressed, regulated by mutant B-RAF, and required for cell growth. We show that Skp2 depletion in melanoma cells resulted in a tetraploid cell cycle arrest. Surprisingly, co-knockdown of p27 Kip1 or cyclin E1 failed to prevent the tetraploid arrest induced by Skp2 knockdown. Enhanced Aurora A phosphorylation and repression of G2/M regulators cyclin B1, cyclin-dependent kinase 1, and cyclin A indicated a G2/early M phase arrest in Skp2-depleted cells. Furthermore, expression of nuclear localized cyclin B1 prevented tetraploid accumulation after Skp2 knockdown. The p53 status is most frequently wild type in melanoma, and the tetraploid arrest and down-regulation of G2/M regulatory genes were strongly dependent on wild-type p53 expression. In mutant p53 melanoma lines, Skp2 depletion did not induce cell cycle arrest despite up-regulation of p27 Kip1 . These data indicate that elevated Skp2 expression may overcome p53-dependent cell cycle checkpoints in melanoma cells and highlight Skp2 actions that are independent of p27 Kip1 degradation. INTRODUCTIONUbiquitin-mediated proteolysis of cell cycle regulators is critical for tight control of normal cell proliferation. The rate-limiting step in ubiquitin-dependent degradation is substrate recognition by E3 ubiquitin ligases. Altered expression and/or activity of E3 ubiquitin ligases in cancer cells leads to deregulated proteolysis and aberrant proliferation (Guardavaccaro and Pagano, 2004;Nakayama and Nakayama, 2006). It is critical to understand how E3 ubiquitin ligases contribute to malignant cell proliferation, because they represent a potential new class of therapeutic targets (Nalepa et al., 2006).One major class of E3 ubiquitin ligases that regulates cell cycle progression contains Skp1/Cullin/F-box protein (SCF) complexes (Krek, 1998;Patton et al., 1998). Within these complexes, the cullin protein serves as a scaffold for the E2 ubiquitin-conjugating enzyme and Skp1/F-box protein complex. The F-box protein determines the substrate specificity of the SCF complex; ϳ70 exist in the human genome. The F-box protein S phase kinase-associated protein 2 (Skp2) has received attention as a putative oncogene. Its expression correlates with tumor malignancy in several tumor types, and the SKP2 gene is amplified in small cell lung and biliary tract cancers (reviewed in Guardavaccaro and Pagano, 2004). High expression of Skp2 is sufficient to promote anchorage-independent growth (Carrano et al., 1999), and Skp2 cooperates with mutant Ras to transform rat fibroblasts (Gstaiger et al., 2001). Evidence from transgenic mice models shows that expression of Skp2 in the T-lymphoid lineage cooperates with activate...

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Section: Discussionmentioning

confidence: 99%

Skp2 Regulates G2/M Progression in a p53-dependent Manner

Aplin

2008

MBoC

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“…Collective efforts from the research community identified at least 12 types of protein post-translational modifications (PTMs), 1 most of which were identified by mass spectrometry (1,(3)(4)(5). In addition, the search for histone PTMs has not been exhausted and, not only novel sites, but also novel types of modifications continue to be discovered.…”

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Lysine Succinylation and Lysine Malonylation in Histones

Xie

Dai

et al. 2012

Molecular & Cellular Proteomics

495

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Histone protein post-translational modifications (PTMs) are significant for gene expression and DNA repair. Here we report the identification and validation of a new type of PTM in histones, lysine succinylation. The identified lysine succinylated histone peptides were verified by MS/MS of synthetic peptides, HPLC co-elution, and isotopic labeling. We identified 13, 7, 10, and 7 histone lysine succinylation sites in HeLa, mouse embryonic fibroblast, Drosophila S2, and Saccharomyces cerevisiae cells, respectively. We demonstrated that this histone PTM is present in all eukaryotic cells we examined. Mutagenesis of succinylation sites followed by functional assays implied that histone lysine succinylation can cause unique functional consequences. We also identified one and two histone lysine malonylation sites in HeLa and S. cerevisiae cells, respectively. Our results therefore increase potential combinatorial diversity of histone PTMs and suggest possible new connections between histone biology and metabolism. Molecular & Cellular

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“…Posttranslational modification of p53 is another important mechanism for its regulation (6). p53 modification by phosphorylation, acetylation, methylation, sumoylation, and neddylation may disrupt p53-Mdm2 interaction or inhibit p53 ubiquitination if the same lysine residues are modified by acetylation (12). It is noteworthy that all known E3 ligases are negative regulators of p53 by promoting p53 degradation, which is inhibited in response to DNA damage.…”

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RFWD3–Mdm2 ubiquitin ligase complex positively regulates p53 stability in response to DNA damage

Yucer

Liu

et al. 2010

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

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In unstressed cells, the tumor suppressor p53 is maintained at low levels by ubiquitin-mediated proteolysis mainly through Mdm2. In response to DNA damage, p53 is stabilized and becomes activated to turn on transcriptional programs that are essential for cell cycle arrest and apoptosis. Activation of p53 leads to accumulation of Mdm2 protein, a direct transcriptional target of p53. It is not understood how p53 is protected from degradation when Mdm2 is upregulated. Here we report that p53 stabilization in the late phase after ionizing radiation correlates with active ubiquitination. We found that an E3 ubiquitin ligase RFWD3 (RNF201/FLJ10520) forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and is required to stabilize p53 in the late response to DNA damage. This process is regulated by the DNA damage checkpoint, because RFWD3 is phosphorylated by ATM/ATR kinases and the phosphorylation mutant fails to stimulate p53 ubiquitination. In vitro experiments suggest that RFWD3 is a p53 E3 ubiquitin ligase and that RFWD3-Mdm2 complex restricts the polyubiquitination of p53 by Mdm2. Our study identifies RFWD3 as a positive regulator of p53 stability when the G 1 cell cycle checkpoint is activated and provides an explanation for how p53 is protected from degradation in the presence of high levels of Mdm2.T he p53 tumor suppressor is a key regulator of cell cycle arrest and apoptosis in response to genotoxic stress (1-3). The G 1 cell cycle checkpoint is operated through the p53-dependent transcriptional response (4). Accumulation of the p53 target gene product p21 WAF1∕CIP1 after DNA damage to a suprathreshold level, capable of blocking the G 1 -S promoting cyclinE/Cdk2 activity, may require several hours and is responsible for the sustained G 1 arrest (5).p53 is primarily regulated at the level of protein stability (6, 7). At least five E3 ligases (E6-AP, Mdm2, Arf-BP1, COP1, and Pirh2) have been identified to mediate ubiquitin-dependent proteasomal degradation of p53. Each of the E3 ligases is capable of building K48-linked polyubiquitin chains on p53, which are recognized by 26S proteasome for degradation. In response to DNA damage, it is thought that such polyubiquitination is inhibited to stabilize p53 protein. Mdm2 is the major p53 E3 ligase, because embryonic lethality of Mdm2-knockout mice caused by p53-induced apoptosis is rescued by deletion of p53 (8, 9).One paradox exists in the Mdm2 axis for p53 stabilization. Because Mdm2 is a p53 transcription target, stabilization of p53 leads to up-regulation of Mdm2 (10), which in turn should degrade p53, but p53 is maintained at high levels when the G 1 checkpoint is active. It was proposed that DNA damage destabilizes Mdm2 by a mechanism involving phosphorylation by ATM/ ATR and increased Mdm2 turnover. Thus, accelerated Mdm2 ubiquitination shortens its half-life, suppressing its activity towards p53 (11). Posttranslational modification of p53 is another important mechanism for its regulation (6). p53 modification by phosphorylation, acetylation, ...

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SnapShot: p53 Posttranslational Modifications

Cited by 141 publications

References 10 publications

Skp2 Regulates G2/M Progression in a p53-dependent Manner

Skp2 Regulates G2/M Progression in a p53-dependent Manner

Lysine Succinylation and Lysine Malonylation in Histones

RFWD3–Mdm2 ubiquitin ligase complex positively regulates p53 stability in response to DNA damage

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