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)

The p53 protein accumulates in human skin cells in vitro and in vivo when UV-irradiated. The transient stability of p53 requires a decrease in the activity of the ubiquitin ligase murine double minute 2 (Mdm2). Solar light irradiation (52.5, 105 and 405 mJ/cm2) of reconstructed human epidermis caused cutaneous damage. Specifically, UV-B induced the formation of sunburn cells and at first, an increase in the accumulation of p53 protein. Unexpectedly, 24 h after irradiation, a specific proteolytic cleavage of p53 resulted in the formation of a 40 kDa fragment. Both the accumulation of p53 and the proteolytic cleavage increased, commensurate with the UV dose. In contrast to p53, the level of expression of Mdm2 decreased drastically with the UV dose. It is important to note that calpastatin (20 microM), a specific inhibitor of calpains, decreased the formation of sunburn cells, inhibited the cleavage of p53 and induced an accumulation of Mdm2. The apoptotic process is strongly repressed. This demonstrates for the first time that calpains can participate in the down-regulation of Mdm2 in the epidermis very rapidly after UV irradiation, and that they contribute to a specific cleavage of p53 protein. All of these processes may be involved in the apoptotic response of the skin to UV stimulation.
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PMID:The contribution of calpains in the down-regulation of Mdm2 and p53 proteolysis in reconstructed human epidermis in response to solar irradiation. 1580 33

Myeloid leukemia factor 1 (MLF1) was first identified as the leukemic fusion protein NPM-MLF1 generated by the t(3;5)(q25.1;q34) chromosomal translocation. Although MLF1 expresses normally in a variety of tissues including hematopoietic stem cells and the overexpression of MLF1 correlates with malignant transformation in human cancer, little is known about how MLF1 is involved in the regulation of cell growth. Here we show that MLF1 is a negative regulator of cell cycle progression functioning upstream of the tumor suppressor p53. MLF1 induces p53-dependent cell cycle arrest in murine embryonic fibroblasts. This action requires a novel binding partner, subunit 3 of the COP9 signalosome (CSN3). A reduction in the level of CSN3 protein with small interfering RNA abrogated MLF1-induced G1 arrest and impaired the activation of p53 by genotoxic stress. Furthermore, ectopic MLF1 expression and CSN3 knockdown inversely affect the endogenous level of COP1, a ubiquitin ligase for p53. Exogenous expression of COP1 overcomes MLF1-induced growth arrest. These results indicate that MLF1 is a critical regulator of p53 and suggest its involvement in leukemogenesis through a novel CSN3-COP1 pathway.
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PMID:Myeloid leukemia factor 1 regulates p53 by suppressing COP1 via COP9 signalosome subunit 3. 1586 Nov 29

Cervical cancers evolve from lesions generated by genital human papillomaviruses (HPV). "Low-risk" genital HPVs cause benign proliferations whereas "high-risk" types have the potential to progress into cancer. High-risk HPV E6 oncoproteins interact with the ubiquitin ligase E6AP and target several cellular proteins, including p53 and proteins of the MAGI family, towards ubiquitin-mediated degradation. E6AP, like other E6 binding proteins such as E6BP, IRF-3 and paxillin, interacts with E6 via a consensus leucine-charged motif. Here we have investigated the kinetics of the interactions of a 15-mer peptide containing the LxxvarphiLsh motif of E6AP with E6. For this we have developed a Biacore assay based on antibody-capture on the sensor surface of GST- and/or MBP-E6AP peptide constructs followed by E6 protein injection. Our experiments show that E6 oncoproteins from four major high-risk (16, 18, 33 and 58) HPV types bind to E6AP with equilibrium dissociation constants in the low micromolar range. The kinetic dissociation parameters of these interactions are remarkably similar. On the other hand, low-risk HPV 11 E6 does not interact with E6AP even at relatively high concentrations. We also show that the two zinc-binding domains of E6 are required for E6AP recognition. Finally, we have analysed the binding properties of site-directed mutants of the E6AP-derived peptide. We demonstrate the importance for binding of conserved aliphatic side-chains and the moderate role of the global negative charge of the peptide. This work provides the first quantitative data on an HPV E6-mediated interaction, which support the current models of E6AP-mediated degradation.
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PMID:Kinetic analysis of the interactions of human papillomavirus E6 oncoproteins with the ubiquitin ligase E6AP using surface plasmon resonance. 1589 Feb 4

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

The cellular level of the tumor suppressor p53 is tightly regulated through induced degradation via the ubiquitin/proteasome system. The ubiquitin ligase Mdm2 plays a pivotal role in stimulating p53 turnover. However, recently additional ubiquitin ligases have been identified that participate in the degradation of the tumor suppressor. Apparently, multiple degradation pathways are employed to ensure proper destruction of p53. Here we show that the chaperone-associated ubiquitin ligase CHIP is able to induce the proteasomal degradation of p53. CHIP-induced degradation was observed for mutant p53, which was previously shown to associate with the chaperones Hsc70 and Hsp90, and for the wild-type form of the tumor suppressor. Our data reveal that mutant and wild-type p53 transiently associate with molecular chaperones and can be diverted onto a degradation pathway through this association.
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PMID:The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation. 1591 28

The p53 tumor suppressor protein has a major role in protecting the integrity of the genome. In unstressed cells, p53 is maintained at low levels by the ubiquitin-proteasome pathway. A balance between ubiquitin ligase activity (Hdm2, COP1, and Pirh2) and the ubiquitin protease activity of the Herpes virus-associated ubiquitin-specific protease (HAUSP) determines the half-life of p53. HAUSP also modulates p53 stability indirectly by deubiquitination and stabilization of Hdm2. The Hdmx protein affects p53 stability as well through its interaction with and regulation of Hdm2. Vice versa, Hdmx is a target for Hdm2-mediated ubiquitination and degradation. Here, we show that HAUSP also interacts with Hdmx, resulting in its direct deubiquitination and stabilization. HAUSP activity is required to maintain normal Hdmx protein levels. Therefore, the balance between HAUSP and Hdm2 activity determines Hdmx protein stability. Importantly, impaired deubiquitination of Hdmx/Hdm2 by HAUSP contributes to the DNA damage-induced degradation of Hdmx and transient instability of Hdm2.
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PMID:Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2. 1591 63

The p53 tumor suppressor protein is regulated by its interaction with HDM2, which serves as a ubiquitin ligase (E3) to target p53 for degradation. We have identified a family of small molecules (HLI98) that inhibits HDM2's E3 activity. These compounds show some specificity for HDM2 in vitro, although at higher concentrations effects on unrelated RING and HECT domain E3s are detectable, which could be due, at least in part, to effects on E2-ubiquitin thiol-ester levels. In cells, the compounds allow the stabilization of p53 and HDM2 and activation of p53-dependent transcription and apoptosis, although other p53-independent toxicity was also observed.
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PMID:Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. 1595 Sep 4

Although the importance of the ARF tumor suppressor in p53 regulation is well established, numerous studies indicate that ARF also suppresses cell growth in a p53/Mdm2-independent manner. To understand the mechanism of ARF-mediated tumor suppression, we identified a ubiquitin ligase, ARF-BP1, as a key factor associated with ARF in vivo. ARF-BP1 harbors a signature HECT motif, and its ubiquitin ligase activity is inhibited by ARF. Notably, inactivation of ARF-BP1, but not Mdm2, suppresses the growth of p53 null cells in a manner reminiscent of ARF induction. Surprisingly, in p53 wild-type cells, ARF-BP1 directly binds and ubiquitinates p53, and inactivation of endogenous ARF-BP1 is crucial for ARF-mediated p53 stabilization. Thus, our study modifies the current view of ARF-mediated p53 activation and reveals that ARF-BP1 is a critical mediator of both the p53-independent and p53-dependent tumor suppressor functions of ARF. As such, ARF-BP1 may serve as a potential target for therapeutic intervention in tumors regardless of p53 status.
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PMID:ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. 1598 44

Constitutively photomorphogenic 1 (COP1), a RING finger ubiquitin ligase with substrates including c-Jun and p53, was recently found to be overexpressed in a number of breast and ovarian tumor samples. In addition to its E3 activity, COP1 was also shown to be able to inhibit activator protein 1 (AP-1) transcription. Through an affinity purification method, we have identified major vault protein (MVP) as a novel interacting partner for COP1 in mammalian cells. MVP, also known as lung resistance protein, is the main component of a ribonucleoprotein organelle called vault, and has been implicated in multiple drug resistance in many cancer cell lines and primary tumor samples. The interaction between COP1 and MVP is detectable at the endogenous level and occurs mostly in the cytoplasm. Similar to COP1, MVP inhibits c-Jun accumulation and AP-1 transcription activity. MVP knockout or knockdown cells contain elevated amount of c-Jun and increased AP-1 transcription activity. UV irradiation enhances MVP tyrosine phosphorylation, causes dissociation of COP1 from MVP, and alleviates the inhibitory activity of MVP on AP-1 transcription. Taken together, we propose that MVP, most likely through its interaction with COP1, suppresses c-Jun-mediated AP-1 transcription under unstressed conditions, thereby preventing cells from undergoing stress response.
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PMID:Major vault protein, in concert with constitutively photomorphogenic 1, negatively regulates c-Jun-mediated activator protein 1 transcription in mammalian cells. 1599 60

The study describes the protein kinase selectivity profile, as well as the binding mode of olomoucine II in the catalytic cleft of CDK2, as determined from cocrystal analysis. Apart from the main cell cycle-regulating kinase CDK2, olomoucine II exerts specificity for CDK7 and CDK9, with important functions in the regulation of RNA transcription. In vitro anticancer activity of the inhibitor in a panel of tumor cell lines shows a wide potency range with a slight preference for cells harboring a wild-type p53 gene. Cell-based assays confirmed activation of p53 protein levels and events leading to accumulation of p21(WAF1). Additionally, in olomoucine II-treated cells, Mdm2 was found to form a complex with the ribosomal protein L11, which inhibits Mdm2 ubiquitin ligase function. We conclude that perturbations in RNA synthesis may lead to activation of p53 and that this contributes to the antiproliferative potency of cyclindependent kinase inhibitors.
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PMID:Antiproliferative activity of olomoucine II, a novel 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitor. 1600 86


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