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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SUMO, a small ubiquitin-related modifier, is known to covalently attach to a number of nuclear regulatory proteins such as p53, IkappaB, promyelocytic leukemia protein and c-Jun. The sumoylation reaction is catalyzed by the SUMO protease, which exposes the C-terminal active glycine residue of the nascent SUMO, the heterodimeric SUMO activating enzyme, the SUMO conjugating enzyme, Ubc9, and SUMO protein ligases, in a manner similar to ubiquitinylation. Identification of SUMO-regulated proteins is hampered by the fact that many sumoylated proteins are present at a level below normal detection limit. This limitation was overcome by either in vivo overexpression of Myc-SUMO or in vitro sumoylation with excess biotin-SUMO and Ubc9. Sumoylated proteins so obtained were affinity purified or isolated by immunoprecipitation. The isolated sumoylated proteins were identified by sequence analysis using mass spectrometric methods. Results reveal that several heterogeneous nuclear ribonucleoproteins (hnRNPs), zinc finger proteins, and nuclear pore complex proteins were sumoylated. The sumoylation of hnRNP A1, hnRNP F, and hnRNP K were confirmed in vivo by coimmunoprecipitation. In view of the facts that hnRNPs have been implicated in RNA splicing, transport, stability, and translation, our findings suggest that sumoylation could play an important role in regulating mRNA metabolism.
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PMID:Sumoylation of heterogeneous nuclear ribonucleoproteins, zinc finger proteins, and nuclear pore complex proteins: a proteomic analysis. 1516 80

The tumor suppressor and transcriptional regulator p53 is perhaps one of the most regulated proteins in the cell nucleus and is acted upon by a variety of protein kinases, acetylases, ubiqutin ligases and hydrolases, and SUMO-conjugating enzymes. Now new work suggests a role for an additional modification-neddylation-in negative regulation of p53 transcriptional activity.
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PMID:Neddylating the guardian; Mdm2 catalyzed conjugation of Nedd8 to p53. 1524 46

Small ubiquitin-like modifier-1 (SUMO-1) conjugation to the tumor suppressor protein p53 seems to be regulated by murine double minute 2 homologue (Mdm2). It is thought that the physical association of Mdm2 with p53 is important for the enhancement of SUMO-1 conjugation to p53. However, mutant p53 that does not associate with Mdm2 is still sumoylated, albeit at a reduced level, suggesting that sumoylation of p53 is independent of the presence of Mdm2 and there is a direct association of ubiquitin-conjugating enzyme 9 (Ubc9), an E2 ligase for sumoylation, with p53. Here, we report evidence of the direct interaction of Ubc9 with p53. Furthermore, we observed that the interaction of Ubc9 with p53 was regulated by phosphorylation of p53. In particular, in cells treated with adriamycin that is a DNA damaging agent and that enhances phosphorylation of p53 at Ser-20, SUMO conjugation of p53 was severely impaired possibly by reduced affinity of Ubc9 to p53.
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PMID:Association of Ubc9, an E2 ligase for SUMO conjugation, with p53 is regulated by phosphorylation of p53. 1532 68

SUMO (small ubiquitin-related modifier) family proteins are not only structurally but also mechanistically related to ubiquitin in that they are posttranslationally attached to other proteins. As ubiquitin, SUMO is covalently linked to its substrates via amide (isopeptide) bonds formed between its C-terminal glycine residue and the epsilon-amino group of internal lysine residues. The enzymes involved in the reversible conjugation of SUMO are similar to those mediating the ubiquitin conjugation. Since its discovery in 1996, SUMO has received a high degree of attention because of its intriguing and essential functions, and because its substrates include a variety of biomedically important proteins such as tumor suppressor p53, c-jun, PML and huntingtin. SUMO modification appears to play important roles in diverse processes such as chromosome segregation and cell division, DNA replication and repair, nuclear protein import, protein targeting to and formation of certain subnuclear structures, and the regulation of a variety of processes including the inflammatory response in mammals and the regulation of flowering time in plants.
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PMID:SUMO protein modification. 1557 12

The SIR2 family of nicotinamide adenosine dinucleotide (NAD)-dependent deacetylases modulates diverse biological functions in different species, including longevity, apoptosis, cell cycle exit, and cellular differentiation. SIRT1, the closest mammalian ortholog of the yeast SIR2 (silent information regulator 2) gene, represses several transcription factors, including p53, NFkappaB and forkhead proteins. The p300 protein serves as a rate-limiting transcriptional cointegrator of diverse transcription factors either to activate or to repress transcription through modular subdomains. Herein, SIRT1 physically interacted with and repressed p300 transactivation, requiring the NAD-dependent deacetylase activity of SIRT1. SIRT1 repression involved the CRD1 transcriptional repression domain of p300. Two residues within the CRD1 domain (Lys-1020 and Lys-1024) were required for SIRT1 repression and served as substrates for SIRT1 deacetylation. These residues also serve as acceptor lysines for modification by the ubiquitin-like SUMO protein. The SUMO-specific protease SSP3 relieved SIRT1 repression of p300. SSP3 antagonism of SIRT1 required the SUMO-deconjugating function of SSP3. Thus, p300 serves as a deacetylase substrate for SIRT1 through a conserved SUMO consensus motif. Because p300 is a limiting transcriptional cofactor, deacetylation and repression of p300 by SIRT1 may serve an important integration point during metabolism and cellular differentiation.
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PMID:SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1. 1563 93

We have recently identified the p53-related DeltaNp63 gene as a transcriptional target of Bmp signaling that encodes a transcriptional repressor blocking neural development in the zebrafish ectoderm. However, in contrast to Bmps, the neural-repressing effect of forced DeltaNp63alpha expression is restricted to the presumptive forebrain, while posterior regions of the brain are not affected. Here, we show that this is due to instability of DeltaNp63alpha protein on the dorsal side of the embryo. In a yeast-two-hybrid screen, we isolated two DeltaNp63alpha-modifying enzymes, the SUMO-conjugating enzyme Ubc9 and the ubiquitin ligase Nedd4. The proteins bind to distinct sites in the C-terminal region of DeltaNp63alpha, which are absent in the shorter and more stable DeltaNp63gamma isoform. Similarly, mutant versions of DeltaNp63alpha unable to bind Nedd4 or Ubc9 are stabilized. DeltaNp63alpha is sumoylated and ubiquitinated both in HEK293 cells and in zebrafish embryos, and Nedd4 promotes ubiquitination and instability of DeltaNp63alpha protein, with lysine residue 637 serving as a potential alternative sumoylation and ubiquitination site that is crucial for DeltaNp63alpha destabilization. In zebrafish, ubc9.1 and nedd4 show restricted expression on the dorsal side of the embryo, where DeltaNp63alpha instability can be overcome upon blockage of endogenous Nedd4 activity, or upon injection of mutant versions of DeltaNp63alpha that are unable to bind Nedd4 or Ubc9. This results in a more widespread neural repression, affecting the entire Bmp-sensitive neuroectoderm. In sum, our data indicate that DeltaNp63alpha is ubiquitinated in a Nedd4- and sumoylated in a Ubc9-dependent fashion, and that these modifications can regulate DeltaNp63alpha stability in the zebrafish ectoderm.
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PMID:Destabilization of DeltaNp63alpha by Nedd4-mediated ubiquitination and Ubc9-mediated sumoylation, and its implications on dorsoventral patterning of the zebrafish embryo. 1590 75

Homeodomain-interacting protein kinase 2 (HIPK2) is involved in transcriptional regulation, growth suppression, and apoptosis. Previous reports showed that HIPK2 can signal cell death via p53, and independently of p53 by activating the c-Jun NH2-terminal kinase (JNK) pathway or mediating CtBP degradation. Here we demonstrate that human HIPK2 is small ubiquitin-related modifier-1 (SUMO-1)-modified in vitro and in vivo at lysine residue 25, a SUMO consensus modification motif conserved in human and mouse HIPK family proteins. SUMO modification of HIPK2 altered neither its nuclear body localization nor its recruitment to promyelocytic leukemia-nuclear bodies. However, SUMO-1 modification inhibited HIPK2-induced JNK activation and p53-independent antiproliferative function. HIPK2 with a mutated SUMO acceptor lysine residue was refractory to inhibition of HIPK2-mediated JNK activation by SUMO-1. Furthermore, we demonstrate that SUMO protease SuPr-1 interacts with HIPK2, and both proteins predominantly colocalize in promyelocytic leukemia-nuclear bodies. SuPr-1 deconjugates SUMO-1 from HIPK2 in vitro and in vivo, which results in modestly increased HIPK2-induced JNK activity. Thus, our data demonstrate that HIPK2 effector function on JNK is modulated through dynamic SUMO-1 modification.
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PMID:Regulation of homeodomain-interacting protein kinase 2 (HIPK2) effector function through dynamic small ubiquitin-related modifier-1 (SUMO-1) modification. 1595 89

Cellular senescence and apoptosis have evolved to restrain unwarranted proliferation of potentially tumorigenic cells. Here we show that overexpression of the E3 SUMO ligase PIASy in normal human fibroblasts recruits the p53 and Rb tumor suppressor pathways to provoke a senescence arrest. By contrast, in Rb-deficient fibroblasts, expression of PIASy leads to p53-dependent apoptosis. Induction of senescence requires PIASy E3 activity and is specific for this member of the PIAS ligase family. PIASy stimulates sumoylation and transcriptional activity of p53 and increases Rb-dependent corepression through recruitment to E2F-responsive promoters. Viral oncoprotein E6 suppresses both PIASy-induced senescence and sumoylation of PIASy substrates. Finally, we show that fibroblasts lacking PIASy exhibit a highly reduced propensity to undergo senescence in response to a prosenescence stimulus. Altogether, these data provide the first evidence for a direct role of an E3 SUMO ligase, and by implication of the SUMO pathway, in cellular senescence and apoptosis.
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PMID:The E3 SUMO ligase PIASy is a regulator of cellular senescence and apoptosis. 1679 47

The p53 tumour suppressor has a key role in the control of cell growth and differentiation, and in the maintenance of genome integrity. p53 is kept labile under normal conditions, but in response to stresses, such as DNA damage, it accumulates in the nucleus for induction of cell-cycle arrest, DNA repair or apoptosis. Mdm2 is an ubiquitin ligase that promotes p53 ubiquitination and degradation. Mdm2 is also self-ubiquitinated and degraded. Here, we identified a novel cascade for the increase in p53 level in response to DNA damage. A new SUMO-specific protease, SUSP4, removed SUMO-1 from Mdm2 and this desumoylation led to promotion of Mdm2 self-ubiquitination, resulting in p53 stabilization. Moreover, SUSP4 competed with p53 for binding to Mdm2, also resulting in p53 stabilization. Overexpression of SUSP4 inhibited cell growth, whereas knockdown of susp4 by RNA interference (RNAi) promoted of cell growth. UV damage induced SUSP4 expression, leading to an increase in p53 levels in parallel with a decrease in Mdm2 levels. These findings establish a new mechanism for the elevation of cellular p53 levels in response to UV damage.
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PMID:SUMO-specific protease SUSP4 positively regulates p53 by promoting Mdm2 self-ubiquitination. 1708 74

As a multifunctional protein, Yin Yang 1 (YY1) has been demonstrated to regulate both gene expression and protein posttranslational modifications. However, gaps still exist in our knowledge of how YY1 can be modified and what the consequences of its modifications are. Here we report that YY1 protein can be sumoylated both in vivo and in vitro. We have identified lysine 288 as the major sumoylation site of YY1. We also discovered that PIASy, a SUMO E3 ligase, is a novel YY1-interacting protein and can stimulate the sumoylation of YY1 both in vitro and in vivo. Importantly, the effects of PIASy mutants on in vivo YY1 sumoylation correlate with the YY1-PIASy interaction but do not depend on the RING finger domain of PIASy. This regulation is unique to YY1 sumoylation because PIASy-mediated p53 sumoylation still relies on the integrity of PIASy, which is also true of all of the previously identified substrates of PIASy. In addition, PIASy colocalizes with YY1 in the nucleus, stabilizes YY1 in vivo, and differentially regulates YY1 transcriptional activity on different target promoters. This study demonstrates that YY1 is a target of SUMOs and reveals a novel feature of a SUMO E3 ligase in the PIAS family that selectively stimulates protein sumoylation independent of the RING finger domain.
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PMID:PIASy-mediated sumoylation of Yin Yang 1 depends on their interaction but not the RING finger. 1735 73


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