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 interacts with a number of cellular proteins to form complexes which are probably crucial for its normal physiological function involving cell cycle control, gene regulation, cell differentiation, apoptosis and tumor suppression. To identify these proteins, we used the yeast two-hybrid system and screened a HeLa cDNA library. Six positive colonies were isolated from 1.5x10(6) transformants. The cDNA sequence of each positive colony was determined. Two novel cDNA fragments (p53BP1 and p53BP2) were cloned. These two cDNA fragments code for the same protein composed of 158 amino acids, which shows high similarity to the ubiquitin-conjugating enzyme (UBC9) of H. sapiens as well as to E2s from other organisms, such as UBC (76 %) of C. elegans, HUS5(66 %) of S. pombe, UBC(66 %) of A. thaliana and UBC9(56 %) of S. cerevisiae. A cDNA fragment from p53BP1 was used to probe a Northern blot containing poly(A)(+) RNA from various human tissues and various cell lines. At high stringency this probe hybridized to a single mRNA of approximately 1.2 kb that was expressed in heart, brain, placenta, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocyte, human cervical carcinoma cell (HeLa), human mammary carcinoma cell (MCF-7), human lymphoma cell (Jurkatt) and human teratocarcinoma cell (PA-I). It is not expressed in brain, lung, human lung carcinoma cell, human heptocellular carcinoma cell (HepG2) and human glioma cell(U251MG).
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PMID:A Novel cDNA Encoding Ubiquitin-conjugating Enzyme of Homo sapiens. 1217 72

UBE1 is known as the human ubiquitin-activating enzyme (E1), which activates ubiquitin in an ATP-dependent manner. Here, we identified a novel human ubiquitin-activating enzyme referred to as UBE1L2, which also shows specificity for ubiquitin. The UBE1L2 sequence displays a 40% identity to UBE1 and also contains an ATP-binding domain and an active site cysteine conserved among E1 family proteins. UBE1L2 forms a covalent link with ubiquitin in vitro and in vivo, which is sensitive to reducing conditions. In an in vitro polyubiquitylation assay, recombinant UBE1L2 could activate ubiquitin and transfer it onto the ubiquitin-conjugating enzyme UbcH5b. Ubiquitin activated by UBE1L2 could be used for ubiquitylation of p53 by MDM2 and supported the autoubiquitylation of the E3 ubiquitin ligases HectH9 and E6-AP. The UBE1L2 mRNA is most abundantly expressed in the testis, suggesting an organ-specific regulation of ubiquitin activation.
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PMID:UBE1L2, a novel E1 enzyme specific for ubiquitin. 1758 Mar 10

We previously performed SEREX (serological identification of antigens by recombinant expression cloning) using the sera of patients with esophageal squamous cell carcinoma (SCC), and isolated a variant clone (AK093616) of ubiquitin-conjugating enzyme E21 (UBE2I). This clone was tentatively designated as UBE2I-v5 and analyzed for biological function by transient transfection of the cDNA into activated Ha-ras-transformed NIH3T3 (ras-NIH) mouse fibroblasts. Chemosensitivity to 92 cytotoxic drugs was compared between UBE2I-v5-transfected cells and the parental ras-NIH cells. The UBE2I-v5-transfected cells were more sensitive than the parental cells to anticancer drugs such as vincristine (VCR), mitoxantrone (MIT) and etoposide (VP16). The regression analysis of the total chemosensitivity pattern of UBE2I-vS-transfected cells revealed that the function of UBE2I-v5 was positively related to RPA2 (replication protein A2), Rho-GDI (Rho guanine nucleotide dissociation inhibitor a), FUS (putative tumor suppressor) and TKT (transketolase) but negatively related to Per-1 (period-I), Ran (nuclear Ras-related protein), PTEN (phosphatase and tensin homolog), C/EBPalpha (CCAAT/enhancer binding protein a) and the tumor suppressor p53. Thus, it is possible that UBE21-v5 plays a role in carcinogenesis by suppressing the function of CIEBPa and/or p53 via RPA2-like activity.
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PMID:Sensitization against anticancer drugs by transfection with UBE2I variant gene into ras-NIH3H3 mouse fibroblasts. 1797 65

Phosphorylation and small ubiquitin-like modifier (SUMO) conjugation contribute to the spatial and temporal regulation of substrates containing phosphorylation-dependent SUMO consensus motifs (PDSMs). Myocyte-enhancement factor 2 (MEF2) is a transcription factor and PDSM substrate whose modification by SUMO drives postsynaptic dendritic differentiation. NMR analysis revealed that the human SUMO E2 interacted with model substrates for phosphorylated and nonphosphorylated MEF2 in similar extended conformations. Mutational and biochemical analysis identified a basic E2 surface that enhanced SUMO conjugation to phosphorylated PDSM substrates MEF2 and heat-shock transcription factor 1 (HSF1), but not to nonphosphorylated MEF2 or HSF1, nor the non-PDSM substrate p53. Mutant ubiquitin-conjugating enzyme UBC9 isoforms defective in promoting SUMO conjugation to phosphorylated MEF2 in vitro and in vivo also impair postsynaptic differentiation in organotypic cerebellar slices. These data support an E2-dependent mechanism that underlies phosphorylation-dependent SUMO conjugation in pathways that range from the heat-shock response to nuclear hormone signaling to brain development.
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PMID:A molecular basis for phosphorylation-dependent SUMO conjugation by the E2 UBC9. 1968 1

The related RING domain proteins MdmX and Mdm2 are best known for their role as negative regulators of the tumor suppressor p53. However, although Mdm2 functions as a ubiquitin ligase for p53, MdmX does not have appreciable ubiquitin ligase activity. In this study, we performed a mutational analysis of the RING domain of MdmX, and we identified two distinct regions that, when replaced by the respective regions of Mdm2, turn MdmX into an active ubiquitin ligase for p53. Mdm2 and MdmX form homodimers as well as heterodimers with each other. One of the regions identified localizes to the dimer interface indicating that subtle conformational changes in this region either affect dimer stability and/or the interaction with the ubiquitin-conjugating enzyme UbcH5b. The second region contains the cryptic nucleolar localization signal of Mdm2 but is also assumed to be involved in the interaction with UbcH5b. Here, we show that this region has a significant impact on the ability of respective MdmX mutants to functionally interact with UbcH5b in vitro supporting the notion that this region serves two distinct functional purposes, nucleolar localization and ubiquitin ligase activity. Finally, evidence is provided to suggest that the RING domain of Mdm2 not only binds to UbcH5b but also acts as an allosteric activator of UbcH5b.
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PMID:Turning the RING domain protein MdmX into an active ubiquitin-protein ligase. 2070 7

The ubiquitin-proteasome system (UPS) plays a major role in selective protein degradation and regulates various cellular events. Approval of bortezomib for the treatment of multiple myeloma validated the proteasome as an anticancer target. In order to find drug candidates targeting the ubiquitin-dependent protein degradation, we paid an attention to inhibitors against three enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), which are required for polyubiquitination of proteins and prerequisite to proteasome-mediated protein degradation. We succeeded in isolating various compounds with three distinct inhibitory activities against an E1 enzyme reaction, Ubc13 (E2)-Uev1A interaction, and p53-HDM2 (E3) interaction as well as the proteasome inhibitors. We also isolated new alkaloids, notoamides, from a marine-derived Aspergillus sp. Among them, notoamide B and stephacidin A contain a bicyclo[2.2.2]diazaoctane ring in their structures. We proposed this ring is constructed from notoamide E by the intramolecular Diels-Alder (IMDA) reaction. Recently, the isolation of the antipodes of notoamides from the terrestrial Aspergillus has been reported. We propose that each enantiomer is generated by a distinct face-selective IMDA.
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PMID:[Study on natural products for drug development]. 2093 Apr 78

Cadmium (Cd) causes renal dysfunction with damage to kidney proximal tubule cells; however, the precise mechanisms of the toxicity remain unclear. Previously, we found that the expression of Ube2d4 gene, which is a member of the ubiquitin-conjugating enzyme Ube2d family, is suppressed by Cd in NRK-52E rat renal tubular epithelial cells. To investigate the mechanisms of Cd-induced renal toxicity, we examined the effects of Cd on the ubiquitin-proteasome system, particularly the expression and function of Ube2d family members in the NRK-52E cells and mice. Cd markedly decreased the expression of Ube2d1, Ube2d2, Ube2d3 and Ube2d4 prior to the appearance of cytotoxicity in the NRK-52E cells. Cd also dramatically increased p53 protein levels in the cells, without stimulation of p53 gene expression or inhibition of proteasome activity. In addition, Cd induced phosphorylation of p53 and caused apoptosis in the NRK-52E cells. In vivo, we examined the effect of orally administrated Cd for 12 months on the expression of Ube2d genes and accumulation of p53 in the mouse kidney. Chronic Cd exposure also caused suppression of Ube2d genes expression and accumulation of p53. Cd did not induce severe kidney injury, but caused apoptosis in the renal tubules. These results suggest that the Cd-induced accumulation of p53 may be due to inhibition of p53 degradation through the down-regulation of Ube2d family genes, and that Cd induces p53-dependent apoptosis in renal tubular cells. Moreover, Ube2d family members may be one of the critical targets of renal toxicity caused by Cd.
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PMID:Cadmium toxicity is caused by accumulation of p53 through the down-regulation of Ube2d family genes in vitro and in vivo. 2146 46

The ubiquitin-conjugating enzyme Ubc13 together with a Ubc/E2 variant (Uev) form a stable complex and mediate K63-linked polyubiquitination, which is implicated in DNA damage tolerance in yeast and mammalian cells. The zebrafish Danio rerio is a lower vertebrate model organism widely used in the studies of vertebrate development and environmental stress responses. Here we report the identification and functional characterization of two zebrafish UEV genes, Drmms2 and Druev1. Their deduced amino acid sequences indicate that the two UEV genes evolved separately prior to the appearance of vertebrates. Both zebrafish Uevs form a stable complex with DrUbc13 as well as Ubc13s from yeast and human, and are able to promote Ubc13-mediated K63 polyubiquitination in vitro, suggesting that their biochemical activities are conserved. Despite the fact that both zebrafish UEV genes can functionally replace the yeast MMS2 DNA-damage tolerance function, they exhibited differences in DNA-damage response in zebrafish embryos: ablation of DrMms2, but not DrUev1, enhances both spontaneous and DNA-damage induced expression of p53 effectors p21 and mdm2. In addition, DrUbc13 specifically binds Drp53 in an in vitro assay. These observations collectively indicate that zebrafish Mms2 and Ubc13 form a stable complex, which is required for p53-mediated DNA-damage response.
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PMID:Zebrafish Mms2 promotes K63-linked polyubiquitination and is involved in p53-mediated DNA-damage response. 2205 68

Radiation induces cell cycle arrest and/or cell death in mammalian cells. In the present study, we show that Hip2, a ubiquitin-conjugating enzyme, can overcome radiation-induced G2/M cell cycle arrest and trigger the entry into mitosis. Ionizing radiation increased the levels of Hip2 by preventing its degradation but not its gene transcription. The stability of Hip2 in irradiated cells was further confirmed using live cell fluorescence imaging. Flow cytometric and molecular analyses revealed that Hip2 abrogated radiation-induced G2/M arrest, promoting entry into mitosis. Bimolecular fluorescence complementation assays and co-immunoprecipitation experiments showed that Hip2 interacted with and targeted p53 for degradation via the ubiquitin proteasome system, resulting in the activation of cdc2-cyclin B1 kinase to promote mitotic entry. These results contribute to our understanding of the mechanisms that regulate cell cycle progression and DNA damage-induced G2/M checkpoint cellular responses.
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PMID:Hip2 ubiquitin-conjugating enzyme overcomes radiation-induced G2/M arrest. 2393 84

Aberrant functionality of the ubiquitin proteasome system (UPS) has been implicated in the pathology of various neurological disorders. Although it has been reported that the expressions of various UPS components were altered significantly following traumatic brain injury (TBI), detailed information on the subject remains largely unclear. In the study, using microarray assay, we identified a gene encoding ubiquitin-conjugating enzyme E2Q1 (UBE2Q1) that was significantly downregulated during TBI. Western blot and immunohistochemical analyses verified the reduced expression of UBE2Q1 in ipsilateral brain cortex adjacent to the lesion site compared with the contralateral and sham-operated ones. Double-immunofluorescence staining indicated that UBE2Q1 was expressed mainly in the nucleus of neurons, with a minority in astrocytes in normal cortex. In addition, we observed a remarkable reduction in the number of UBE2Q1-positive neurons following brain trauma. Furthermore, we showed that TBI resulted in a significant increase in the levels of p53, bax, p21 and active caspase 3 in brain cortex, which was correlated with decreased expression of UBE2Q1. We also found that knockdown of UBE2Q1 apparently increased the level of p53, whereas overexpressing UBE2Q1 attenuated cellular p53 level in PC12 neuronal cells. Accordingly, interference with UBE2Q1 augmented H2O2-induced apoptosis of PC12 cells. Taken together, our findings indicate that UBE2Q1 might play an important role in the neuropathological process of TBI through modulating p53 signaling.
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PMID:Downregulation of UBE2Q1 is associated with neuronal apoptosis in rat brain cortex following traumatic brain injury. 2416 84


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