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

Over the past years, modification by covalent attachment of SUMO (small ubiquitin-like modifier) has been demonstrated for of a number of cellular and viral proteins. While increasing evidence suggests a role for SUMO modification in the regulation of protein-protein interactions and/or subcellular localization, most SUMO targets are still at large. In this report we show that Topors, a Topoisomerase I and p53 interacting protein of hitherto unknown function, presents a novel cellular target for SUMO-1 modification. In a yeast two-hybrid system, Topors interacted with both SUMO-1 and the SUMO-1 conjugating enzyme UBC9. Multiple SUMO-1 modified forms of Topors could be detected after cotransfection of exogenous SUMO-1 and Topors induced the colocalization of a YFP tagged SUMO-1 protein in a speckled pattern in the nucleus. A subset of these Topors' nuclear speckles were closely associated with the PML nuclear bodies (POD, ND10). A central domain comprising Topors residues 437 to 574 was sufficient for both sumolation and localization to nuclear speckles. One SUMO-1 acceptor site at lysine residue 560 could be identified within this region. However, sumolation-deficient Topors mutants showed that sumolation obviously is not required for localization to nuclear speckles.
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PMID:The DNA topoisomerase I binding protein topors as a novel cellular target for SUMO-1 modification: characterization of domains necessary for subcellular localization and sumolation. 1451 84

While the p53 homologue p73 has been found to be involved in tumorigenesis, the molecular mechanisms involved in this function are still not fully evident. The presence of two distinct promoters allows the formation of two proteins with opposite effects: while TA-p73 shows pro-apoptotic effects, DeltaN-p73 has an evident anti-apoptotic function. The relative expression of the two proteins is in fact related to the prognosis of several cancers. Since both p73 and p63, the other member of the same family, share the ability to interact with each other, it is important to understand the mechanisms that control the degradation and stability of both proteins, and their relative isoforms. p73 and p63 stability is regulated not only by protein modifications (phosphorylation, acetylation) but also by its degradation in the proteasome. To this end, the interaction with Mdm2, p300/CBP, and SUMO-1 are discussed in details.
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PMID:p73 and p63 protein stability: the way to regulate function? 1455 34

Here, we developed a binary vector system that introduces a synthetic SUMO-1 conjugation pathway into Escherichia coli and demonstrated that large amounts of sumoylated Ran GTPase activating protein 1 C-terminal region (RanGAP1-C2), Ran binding protein 2 internal repeat domain, p53 and promyelocytic leukemia were efficiently produced. The sumoylated recombinant RanGAP1-C2 appeared to retain the in vivo properties, since it was specifically sumoylated at lysine 517 as expected from in vivo studies. Our findings indicate the establishment of a biosynthetic route for producing large amounts of sumoylated recombinant proteins that will open up new avenues for studying the biochemical and structural aspects of the SUMO-1 modification pathway.
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PMID:Generation of SUMO-1 modified proteins in E. coli: towards understanding the biochemistry/structural biology of the SUMO-1 pathway. 1509 46

Direct interaction of positive and negative regulators with the general transcription machinery modulates transcription. The TATA-binding protein (TBP) is one target for transcriptional regulators. In this study, we identified ZNF76 as a novel transcriptional repressor that targets TBP. ZNF76 interacts with TBP through both its N and C termini, and both regions are required for ZNF76 to exert its inhibitory function on p53-mediated transactivation. The inhibitory effect of ZNF76 on p53 activity was demonstrated by reporter assays and endogenous target gene expression. We mapped the TBP-interacting region in the C terminus of ZNF76 to a glutamic acid-rich domain, which acts in a dominant negative manner to enhance p53-mediated transactivation in reporter assays. Mutagenesis study for ZNF76 suggests a correlation between interaction with TBP and effect on p53-mediated transactivation, supporting the conclusion that ZNF76 targets TBP for transcriptional repression. Chromatin immunoprecipitation experiments suggest that ZNF76 prevents TBP from occupying the endogenous p21 promoter. ZNF76 is sumoylated by PIAS1 at lysine 411, which is in the minimal TBP-interacting region. Overexpression of PIAS1 and SUMO-1 abolishes the interaction between ZNF76 and TBP and partially relieves the repressive effect of ZNF76. These results suggest that ZNF76 functions as a transcriptional repressor through its interaction with TBP and that sumoylation modulates its transcriptional repression activity.
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PMID:ZNF76, a novel transcriptional repressor targeting TATA-binding protein, is modulated by sumoylation. 1528 Mar 58

The HIPK2 protein is a critical regulator of apoptosis and functionally interacts with p53 to increase gene expression. Here we show that human HIPK2 is modified by sumoylation at lysine 25, as revealed by in vivo and in vitro experiments. While SUMO-1 modification of HIPK2 has no influence on its ability to phosphorylate p53 at serine 46, to induce gene expression, and to mediate apoptosis, a non-sumoylatable HIPK2 mutant displays a strongly increased protein stability. The N-terminal SUMO-1 modification site is conserved between all vertebrate HIPK2 proteins and is found in all members of the HIPK family of protein kinases. Accordingly, also human HIPK3 is modified by sumoylation.
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PMID:Covalent modification of human homeodomain interacting protein kinase 2 by SUMO-1 at lysine 25 affects its stability. 1576 67

MDMX is a homolog of MDM2 and is critical for regulating p53 function during mouse development. MDMX level is regulated by MDM2-mediated poly-ubiquitination, which results in its accelerated degradation after DNA damage or expression of ARF. In this report, we demonstrate that MDMX can be modified by conjugation to SUMO-1 both in vivo and in vitro. We found that double mutation of two lysine residues, K254 and K379, abrogated MDMX sumoylation in vivo. Experiments using the sumoylation-deficient MDMX mutant showed that it undergoes normal ubiquitination and degradation by MDM2, normal nuclear translocation and degradation after DNA damage, and inhibits p53 with wild type efficiency. Therefore, sumoylation is not required for several activities of MDMX under our assay conditions.
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PMID:Modification of MDMX by sumoylation. 1590

Regulation of p53 by the ubiquitin-proteasomal pathway has been studied considerably. Studies have also demonstrated that the ubiquitin-like proteins SUMO-1 and NEDD8 modify p53. Similarly, p63 and p73 are subject to regulation by ubiquitin and ubiquitin-like modifications, and perturbations of these pathways in the regulation of the p53 family have been implicated in tumorigenesis and developmental abnormalities. Here, we provide an overview of the current understanding of the regulation of the p53 family by covalent modification by ubiquitin, SUMO-1, and NEDD8.
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PMID:Ubiquitin and ubiquitin-like modifications of the p53 family. 1692 48

Three highly homologous small ubiquitin-related modifier (SUMO) proteins have been identified in mammals. Modifications of proteins by SUMO-1 have been shown to regulate transcription, nucleocytoplasmic transport, protein stability, and protein-protein interactions. Relative to SUMO-1, little is known about the functions of SUMO-2 or SUMO-3 (referred to as SUMO-2/3). Here, stable cell lines overexpressing processed forms of SUMO-2/3 (SUMO-2/3GG) as well as their non-conjugatable derivatives, SUMO-2/3DeltaGG, were established. Cells overexpressing SUMO-2/3GG showed a premature senescence phenotype as revealed by cellular morphology and senescence-associated galactosidase activity. The senescence pathway protein p21 was up-regulated in cells overexpressing SUMO-2/3GG. In contrast, cells overexpressing non-conjugatable forms of SUMO-2/3DeltaGG showed neither an apparent senescent phenotype nor elevated p21. Both p53 and pRB were found to be modified by SUMO-2/3. Site-directed mutagenesis studies showed that Lys-386 of p53, the SUMO-1 modification site, is also the modification site for SUMO-2/3. In addition, H2O2 treatment of untransfected cells caused an increase in p53 sumoylation by SUMO-2/3, whereas that by SUMO-1 remained unchanged. Moreover, knocking down tumor suppressor proteins p53 or pRB using small interfering RNA significantly alleviated the premature senescence phenotypes in SUMO-2/3GG overexpressing cells. Together, our results reveal that p53 and pRB can be sumoylated by SUMO-2/3 in vivo, and such modification of p53 and pRB may play roles in premature senescence and stress response.
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PMID:Expression of SUMO-2/3 induced senescence through p53- and pRB-mediated pathways. 1701 28

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

Promyelocytic leukemia (PML) nuclear bodies (PML-NBs) are the nuclear structure consisting of various proteins such as PML, SUMO-1, and p53. PML-NBs are implicated in the regulation of tumor suppression, antiviral responses, and apoptosis. In this study, we searched for bioactive metabolites that would promote the formation of PML-NBs in tumor cells. As a result, methyl 2,5-dihydromethylcinnimate (2,5-MeC), a tyrosine kinase inhibitor, enhanced expression and/or stability of PML proteins and induced PML-NB formation in p53 null H1299 cells established from non-small cell lung cancer (NSCLC) and wild-type p53-expressing U2OS cells derived from osteosarcoma. Furthermore, it enhanced apoptosis by exogenously expressed wild type p53 and the expression of p53-responsive genes, such as PUMA and p21, in H1299 cells. 2,5-MeC also activated endogenous p53 and induced apoptosis in U2OS cells. The results suggest that 2,5-MeC is likely to be a promising candidate drug for the clinical treatment of terminal cancer-expressing wild-type p53.
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PMID:Tyrosine kinase inhibitor, methyl 2,5-dihydromethylcinnimate, induces PML nuclear body formation and apoptosis in tumor cells. 1758 3


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