Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p53 functions to prevent malignant progression, in part by inhibiting proliferation or inducing the death of potential tumour cells. One of the most important regulators of p53 is MDM2, a RING domain E3 ligase that ubiquitinates p53, leading to both proteasomal degradation and relocation of p53 from the nucleus to the cytoplasm. Previous studies have suggested that although polyubiquitination is required for degradation, monoubiquitination of p53 is sufficient for nuclear export. Using a p53-ubiquitin fusion protein we show that ubiquitination contributes to two steps before export: exposure of a carboxy-terminal nuclear export sequence (NES), and dissociation of MDM2. Monoubiquitination can directly promote further modifications of p53 with ubiquitin-like proteins and MDM2 promotes the interaction of the SUMO E3 ligase PIASy with p53, enhancing both sumoylation and nuclear export. Our results suggest that modifications such as sumoylation can regulate the strength of the p53-MDM2 interaction and participate in driving the export of p53.
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PMID:C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. 1736 17

The nuclear protein p68 (also known as Ddx5) is a prototypic member of the 'DEAD box' family of RNA helicases, which has been shown to be abnormally expressed and modified in colorectal tumors and to function as an important transcriptional regulator. Here, we show that p68 is modified in vivo on a single site (K53) by the small ubiquitin-like modifier-2 (SUMO-2). We demonstrate that the SUMO E3 ligase PIAS1 interacts with p68 and enhances its SUMO modification in vivo. To determine the functional consequences of SUMO modification, we compared the transcriptional activity of p68 and a K53R mutant that could not be SUMO-modified. Our data show that SUMO modification enhances p68 transcriptional repression activity and inhibits the ability of p68 to function as a coactivator of p53. These findings may be explained by the ability of wild type, but not K53R p68, to alter the modification state of chromatin by recruitment of histone deacetylase 1 (HDAC1).
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PMID:SUMO modification of the DEAD box protein p68 modulates its transcriptional activity and promotes its interaction with HDAC1. 1736 52

The histone acetyltransferase TIP60 regulates the DNA damage response following genotoxic stress by acetylating histone and remodeling chromatin. However, the molecular mechanisms underlying the TIP60-dependent response to UV-induced DNA damage remain poorly understood. To systematically analyse proteins that regulate TIP60 activity in response to UV irradiation, we performed a proteomic analysis of proteins selectively bound to TIP60 in response to UV irradiation using mass spectrometry and identified a novel regulatory mechanism by which TIP60 orchestrates transcriptional activation of p53-dependent checkpoint response in UV-irradiated cells. The initial step of this pathway involves UV-induced association of TIP60 with SUMO-conjugation enzymes and site-specific sumoylation of TIP60 at lysines 430 and 451 via Ubc9. This sumoylation initiates the relocation of TIP60 from nucleoplasm to the promyelocytic leukemia body, which is essential for the UV-irradiated DNA damage repair response via a p53-dependent pathway. Significantly, inhibition of TIP60 sumoylation by overexpression of non-sumoylatable mutant abrogates the p53-dependent DNA damage response, demonstrating the importance of TIP60 sumoylation in response to UV irradiation. Our biochemical characterization demonstrated that the sumoylation of TIP60 augments its acetyltransferase activity in vitro and in vivo. Thus, this study shed new light on the function and regulation of TIP60 activity in UV-irradiated DNA damage response.
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PMID:Functional characterization of TIP60 sumoylation in UV-irradiated DNA damage response. 1770 9

DeltaNp63alpha is exclusively expressed in stem cells and progenitor cells of the stratified epithelia. It promotes cell proliferation by antagonizing p53 and related TAp63/TAp73. Here, we report that specific desumoylation by SUMO protease SuPr-1 provides a fine-tuning mechanism for DeltaNp63alpha repressor activity. We found that disrupting the sumoylation site compromised DeltaNp63alpha repressor activity profoundly against TAp63gamma and TAp73beta-mediated transcription activation, but not to p53-mediated transcription. We further found that SuPr-1 specifically bound to sumoylated DeltaNp63alpha and hydrolyzed SUMO. Consequently, SuPr-1 expression reduced DeltaNp63alpha repressor activity to TAp63gamma and TAp73beta, whereas p53-mediated transactivation was unaffected. Collectively, these data suggest that SuPr-1-mediated DeltaNp63alpha desumoylation elaborately regulates epithelial growth.
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PMID:SuPr-1-mediated desumoylation regulates the repressor activity of DeltaNp63alpha. 1802 81

Carbon nanotubes (CNTs) have shown promise as an important new class of multifunctional building blocks and innovative tools in a large variety of applications, ranging from nanocomposite materials through nanoelectronics to biomedical devices. Because of their unusual one-dimensional hollow nanostructure and unique physicochemical properties, CNTs are particularly useful as novel drug delivery tools and imaging agents. However, such biomedical applications will not be realized if there is no proper assessment of the potential hazards of CNTs to humans and other biological systems. Although a few reports on the cytotoxicity of CNTs have been published, very little is known about the toxicity at the molecular level, or genotoxicity, of CNTs in mammalian cells. We have for the first time assessed the DNA damage response to multiwalled carbon nanotubes (MWNTs) in mouse embryonic stem (ES) cells. We found that MWNTs can accumulate and induce apoptosis in mouse ES cells and activate the tumor suppressor protein p53 within 2 h of exposure. Furthermore, we also observed increased expression of two isoforms of base excision repair protein 8-oxoguanine-DNA glycosylase 1 (OGG1), double strand break repair protein Rad 51, phosphorylation of H2AX histone at serine 139, and SUMO modification of XRCC4 following the treatment with MWNTs. A mutagenesis study using an endogenous molecular marker, adenine phosphoribosyltransferase (Aprt), showed that MWNTs increased the mutation frequency by 2-fold compared with the spontaneous mutation frequency in mouse ES cells. These results suggest that careful scrutiny of the genotoxicity of nanomaterials is needed even for those materials, like multiwalled carbon nanotubes, that have been previously demonstrated to have limited or no toxicity at the cellular level.
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PMID:DNA damage induced by multiwalled carbon nanotubes in mouse embryonic stem cells. 1804 46

The ability of adenovirus to induce cell transformation depends on the E1A and E1B-55K oncoproteins. While E1A functionally inactivates the retinoblastoma tumour suppressor, E1B-55K primarily interferes with the function of p53. In adenovirus transformed cells E1B-55K can directly affect p53-dependent transactivation. In virus-infected cells E1B-55K additionally cooperates with the viral E4orf6 protein to induce ubiquitin-dependent degradation of p53. Here we unravel a novel activity of E1B-55K by demonstrating that it drastically stimulates the post-translational modification of p53 by the ubiquitin-like SUMO modifier. Consistent with this finding the extent of p53 SUMOylation is highly elevated in adenovirus transformed cell lines. E1B-55K-mediated SUMOylation depends on the direct interaction of E1B-55K with p53 and additionally requires SUMO modification of E1B-55K. These data suggest that E1B-55K exploits both ubiquitin and ubiquitin-like systems to target host cell proteins and thus shed new light on the molecular mechanisms of E1B- 55K function. Moreover, the data expand the emerging concept of dual-specificity factors that act in both the SUMO and ubiquitin pathway and identify E1B-55K as the first viral protein that shares this dual activity.
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PMID:The adenovirus E1B-55K oncoprotein induces SUMO modification of p53. 1846 21

Conjugation to SUMO is a reversible post-translational modification that regulates several transcription factors involved in cell proliferation, differentiation, and disease. The p53 tumor suppressor can be modified by SUMO-1 in mammalian cells, but the functional consequences of this modification are unclear. Here, we demonstrate that the Drosophila homolog of human p53 can be efficiently sumoylated in insect cells. We identify two lysine residues involved in SUMO attachment, one at the C terminus, between the DNA binding and oligomerization domains, and one at the N terminus of the protein. We find that sumoylation helps recruit Drosophila p53 to nuclear dot-like structures that can be marked by human PML and the Drosophila homologue of Daxx. We demonstrate that mutation of both sumoylation sites dramatically reduces the transcriptional activity of p53 and its ability to induce apoptosis in transgenic flies, providing in vivo evidence that sumoylation is critical for Drosophila p53 function.
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PMID:Modification of Drosophila p53 by SUMO modulates its transactivation and pro-apoptotic functions. 1849 69

The tumour suppressor p53 has been shown to be modified at its C-terminus with ubiquitin and the ubiquitin-like proteins SUMO and NEDD8. Whereas monoubiquitination of p53 is strongly associated with nuclear export, the effects of sumoylation and neddylation remain unclear. In this study we have generated p53-Ub, p53-SUMO-1 and p53-NEDD8 fusion proteins as models for the effect of these modifications on the localization and function of p53. As shown before, the ubiquitin fusion clearly drives nuclear export of p53 and we now find that this is also partially the case for a SUMO-1 fusion, which does not localise to PML bodies. In contrast a NEDD8 fusion has little effect on nuclear export, and mutating NEDD8 to more closely resemble ubiquitin did not restore nuclear export. Despite their differing subcellular localization, we find that both p53-ubiquitin and p53-NEDD8 retain similar transcriptional activity and both induce apoptosis at a similar level to unfused p53. The p53-ubiquitin fusion protein is potentially a good model for studying the role of p53 outside the nucleus. However, in our experiments we find that the export of p53 from the nucleus is not sufficient to activate its cytoplasmic apoptotic function which may depend on the ability to deubiquitinate cytoplasmic p53.
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PMID:p53-Ubl fusions as models of ubiquitination, sumoylation and neddylation of p53. 1871 71

The PTEN tumour suppressor gene is induced by the early growth response 1 (EGR1) transcription factor, which also transactivates p53, p73, and p300/CBP as well as other proapoptotic and anti-cancer genes. Here, we describe a novel Akt-EGR1-alternate reading frame (ARF)-PTEN axis, in which PTEN activation in vivo requires p14ARF-mediated sumoylation of EGR1. This modification is dependent on the phosphorylation of EGR1 at S350 and T309 by Akt, which promotes interaction of EGR1 with ARF at K272 in its repressor domain by the ARF/Ubc9/SUMO system. EGR1 sumoylation is decreased by ARF reduction, and no EGR1 sumoylation is detected in ARF(-/-) mice, which also exhibit reduced amounts of PTEN. Our model predicts that perturbation of any of the clinically important tumour suppressors, PTEN, EGR1, and ARF, will cause some degree of dysfunction of the others. These results also explain the known negative feedback regulation by PTEN on its own synthesis through PI3 kinase inhibition.
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PMID:PTEN regulation by Akt-EGR1-ARF-PTEN axis. 1905 11

SUMO-specific protease 2 (SENP2) modifies proteins by removing SUMO from its substrates. Although SUMO-specific proteases are known to reverse sumoylation in many defined systems, their importance in mammalian development and pathogenesis remains largely elusive. Here we report that SENP2 is highly expressed in trophoblast cells that are required for placentation. Targeted disruption of SENP2 in mice reveals its essential role in development of all three trophoblast layers. The mutation causes a deficiency in cell cycle progression. SENP2 has a specific role in the G-S transition, which is required for mitotic and endoreduplication cell cycles in trophoblast proliferation and differentiation, respectively. SENP2 ablation disturbs the p53-Mdm2 pathway, affecting the expansion of trophoblast progenitors and their maturation. Reintroducing SENP2 into the mutants can reduce the sumoylation of Mdm2, diminish the p53 level and promote trophoblast development. Furthermore, downregulation of p53 alleviates the SENP2-null phenotypes and stimulation of p53 causes abnormalities in trophoblast proliferation and differentiation, resembling those of the SENP2 mutants. Our data reveal a key genetic pathway, SENP2-Mdm2-p53, underlying trophoblast lineage development, suggesting its pivotal role in cell cycle progression of mitosis and endoreduplication.
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PMID:SUMO-specific protease 2 is essential for modulating p53-Mdm2 in development of trophoblast stem cell niches and lineages. 2007 1


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