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)

Reactivation in Epstein-Barr virus (EBV) is closely associated with a G(0)/G(1) cell cycle arrest which can be induced either by lytic cycle-inducing agents or by the immediate-early gene product Zta. Accumulating evidence shows that in epithelial cells, downregulation of the proto-oncogene, c-myc, plays an important role in lytic cycle-associated cell growth arrest. Here, we provide evidence that c-Myc provides a gatekeeper function to ensure that certain cell cycle inhibitory events have been capitulated prior to full progression into the lytic cycle. Specifically, we show that reconstitution of c-Myc expression during the lytic cycle to levels observed in cycling uninduced cells inhibits the transactivation function of Zta. Nuclear localization studies show that c-Myc does not grossly alter the nuclear localization of Zta or its association with the insoluble nuclear fraction. Enforced expression of another transcription factor that promotes cell cycle progression, E2F1, also inhibits Zta transactivation. Analysis of c-Myc- and E2F1-mediated inhibition of a panel of Zta mutants shows parallel genetics and inhibition maps to a small bipartite sequence located between amino acids 29 and 53 of Zta, containing homology to the proline-rich domain of the tumor suppressor protein p53. Mutation of a conserved tryptophan residue located at amino acid 49 of Zta largely prevents inhibition by both c-Myc and E2F1. These studies identify a negative regulatory element within the Zta activation domain that is regulated by the cell cycle-promoting factors c-Myc and E2F1.
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PMID:Identification of a negative regulatory element in the Epstein-Barr virus Zta transactivation domain that is regulated by the cell cycle control factors c-Myc and E2F1. 1547 36

The BRCA1 tumor suppressor gene encodes an 1863 amino acid gene product that is implicated in many cellular pathways including transcription, cell-cycle checkpoint control, apoptosis and DNA repair. Much attention has been focused on the structural and biochemical characterization of the N-terminal RING and tandem C-terminal BRCT domains of BRCA1. Here we used NMR spectroscopy in conjunction with CD spectroscopy and limited proteolysis to investigate the biophysical properties of the approximately 1500 residue central region of BRCA1. Our results show that although there are a few small, mildly protease-resistant regions, the majority of the BRCA1 central region lacks any pre-existing independently folded globular domains. Electrophoretic mobility shift assay and intrinsic tryptophan fluorescence experiments also demonstrate that, although intrinsically disordered, polypeptides from the central region are able to mediate interactions with DNA and p53 with affinities in the low micromolar range. This supports a model in which the central region may act as a long flexible scaffold for intermolecular interactions, thereby helping to integrate multiple signals in the DNA damage response pathway.
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PMID:Characterization of segments from the central region of BRCA1: an intrinsically disordered scaffold for multiple protein-protein and protein-DNA interactions? 1557 21

We previously demonstrated that restoration of TP53 activity in anaplastic thyroid carcinoma inhibits cell growth and induces expression of thyroid differentiation markers. Here, we investigated whether TP53 status may condition the expression of therapeutic genes driven by retroviral LTR or tissue-specific enhancer elements. The TP53-defective ARO anaplastic thyroid carcinoma cells were transfected with TP53(Val135), which exhibits wild-type activity at 32 degrees C, and transduced with retroviral vectors, in which therapeutic genes were driven either by wild-type LTR or by a reshuffled LTR containing thyroglobulin (TG) enhancer. Both at 37 and 32 degrees C, expression of transgenes driven by TG enhancer was 10-fold lower than that obtained with wild-type LTR retroviral vector. TP53(Val135) transfer into ARO cells repressed transcription from wild-type LTR but increased expression of TG-driven therapeutic genes. This effect was markedly enhanced by cell culture at 32 degrees C and by TSH treatment. Cytotoxic effects shown after ganciclovir treatment paralleled therapeutic gene expression levels. In conclusion, TP53 status in the tumor cell can influence expression of therapeutic genes. When using retroviral-vector-based gene therapy, wild-type LTR vectors should be employed to target TP53-defective tumors, whereas thyroid-specific promoters should be used for transcriptional targeting of thyroid carcinomas carrying wild-type TP53.
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PMID:Modulation of retrovirally driven therapeutic genes by mutant TP53 in anaplastic thyroid carcinoma. 1565 Jul 65

In this early phase of the new era of molecularly targeted patient friendly cancer chemotherapy, there is a need for novel viable anticancer molecular targets. The MDM2 oncoprotein has been validated as a potential target for cancer drug development. MDM2 amplification and/or overexpression occur in a wide variety of human cancers, several of which can be treated experimentally with MDM2 antagonists. MDM2 interacts primarily with the p53 tumor suppressor protein in an autoregulatory negative feedback loop to attenuate p53's cell cycle arrest and apoptosis functions. Inhibition of the p53-MDM2 interaction has been shown to cause selective cancer cell death, as well as sensitize cancer cells to chemotherapy or radiation effects. Consequently, this interaction has been the main focus of anticancer drug discovery targeted to MDM2. The promotion of the proteasomal degradation of the p53 protein by MDM2 is central to its repression of the tumor suppressor functions of p53, and many proteins impinge upon this activity, either enhancing or inhibiting it. MDM2 also has oncogenic activity independent of its interaction with p53, but this has so far not been explored for drug discovery. Among the approaches for targeting MDM2 for cancer therapy, small molecule antagonists have recently featured as effective anticancer agents in experimental models, although the repertoire is currently limited and none has yet entered human clinical trials. Small molecules that have been reported to disrupt the p53-MDM2 binding, thereby enhancing p53 activity to elicit anticancer effects include the following: synthetic chalcones, norbornane derivatives, cis-imidazoline derivatives (Nutlins), a pyrazolidinedione sulfonamide and 1,4-benzodiazepine-2,5-diones, as well as tryptophan derivatives. In addition to compounds disrupting p53pMDM2 binding, three compounds have been discovered that are effective in inhibiting the E3 ligase activity of MDM2 towards p53, and should serve as leads for drug discovery targeting this aspect of the p53-MDM2 interaction as well. These compounds were discovered from library screening and/or structure-based rational drug design strategies.
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PMID:Small molecule antagonists of the MDM2 oncoprotein as anticancer agents. 1572 Jan 90

We previously reported that lysozyme accounts for anti-HIV activity associated with the beta-core fraction of human chorionic gonadotropin [Lee-Huang, S., Huang, P. L., Sun, Y., Kung, H. F., Blithe, D. L. & Chen, H. C. (1999) Proc Natl Acad Sci U S A 96, 2678-81]. To define the structural and sequence requirements for anti-HIV activity, we carried out peptide fragmentation and activity mapping of human lysozyme. We identified two peptides that consist of 18 and 9 amino acids of human lysozyme (HL18 and HL9), corresponding to residues 98-115 and 107-115. HL18 and HL9 are potent inhibitors of HIV-1 infection and replication with EC(50)s of 50 to 55 nM, comparable to intact lysozyme. Scrambling the sequence or substitution of key arginine or tryptophan residues results in loss of antiviral activity. HL9, with the sequence RAWVAWRNR, is the smallest peptide we identified with full anti-HIV activity. It forms a pocket with its basic residues on the surface of the molecule. HL9 exists as an alpha-helix in native human lysozyme, in a region of the protein distinct from the muramidase catalytic site. Monte Carlo peptide folding energy minimizing simulation modeling and CD studies indicate that helical propensity does not correlate with antiviral activity. HL9 blocks HIV-1 viral entrance and replication, and modulates gene expression of HIV-infected cells, affecting pathways involved in survival, stress, TGFbeta, p53, NFkappaB, protein kinase C and hedgehog signaling.
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PMID:Structural and functional modeling of human lysozyme reveals a unique nonapeptide, HL9, with anti-HIV activity. 1577 91

Typically, gene transfer strategies utilize a promoter/transgene arrangement that treat these elements independently and do not offer any interplay between them. Our goal was to establish a promoter/transgene combination that would result in improvement in both expression and therapeutic effect by utilizing the transcriptional properties of p53 to drive its own expression as well as act as a tumor suppressor. The pCL retroviral system was modified in the U3 region of the 3' LTR by the addition of a p53-responsive sequence (the PG element), creating the pCLPG system. Upon reverse transcription, the 5' LTR is converted, as shown here, to a p53-dependent promoter. We also show, using a temperature-sensitive model, that the pCLPG system could be driven by p53 encoded within the virus construct and expression was modulated depending on the p53 phenotype, demonstrating a regulatory feedback loop. Moreover, the pCLPG system was shown to express the transgene at a higher level and to inhibit tumor cell proliferation more robustly than the original pCL system. This novel system employs the transgene to serve two purposes, drive viral expression and inhibit tumor cell proliferation. The pCLPG vectors represent a new gene transfer strategy of synergizing the promoter and transgene activities.
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PMID:A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition. 1590 60

The p53 protein functions as a tumor suppressor, preventing aberrant cellular proliferation in response to various genotoxic and non-genotoxic stress signals. Although p53's ability to induce apoptosis is critical to its capacity to suppress tumorigenesis, the role of transcriptional activation in p53's apoptotic function has been highly controversial. To address this issue, our laboratory generated a p53 mutant knock-in mouse strain in which residues 25 and 26, previously shown to be critical for p53's transactivation function, were mutated from leucine and tryptophan to glutamine and serine, respectively. Our analysis of cells derived from these mice provided significant insight into p53 activity at both the molecular and cellular level. In particular, our data suggest that p53 utilizes discrete mechanisms to transactivate different target genes, and that p53 employs distinct mechanisms to induce apoptosis in response to different stresses. This p53QS mutant mouse strain represents a powerful means to dissect p53 function in vivo.
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PMID:p53QS: an old mutant teaches us new tricks. 1590 88

The tumor-suppressor protein p53 is a major player in regulation of cell growth, genomic stability, and cell death. Recent work suggests that Pseudomonas aeruginosa azurin, as the only bacterial protein known to date, can enter cancer cells and interact with p53 promoting cell death. For the first time, here we demonstrate and characterize this proposed complex using purified proteins in vitro. We find that azurin binds to p53 with nanomolar affinity in a four-to-one stoichiometry (pH 7.5, 25 degrees C). Upon azurin binding, secondary structure is induced and tryptophan fluorescence is quenched, implying that interactions occur in the N-terminal p53 domain which is also the binding site for many oncogenes. Further biophysical studies may assist the design of novel cancer treatments that are based on azurin.
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PMID:Unique complex between bacterial azurin and tumor-suppressor protein p53. 1591 47

Due to the ability to detect multiple parameters simultaneously, protein microarrays have found widespread applications from basic biological research to diagnosis of diseases. Generally, readout of protein microarrays is performed by fluorescence detection using either dye-labeled detector antibodies or direct labeling of the target proteins. We developed a method for the label-free detection and quantification of proteins based on time-gated, wide-field, camera-based UV fluorescence lifetime imaging microscopy to gain lifetime information from each pixel of a sensitive CCD camera. The method relies on differences in the native fluorescence lifetime of proteins and takes advantage of binding-induced lifetime changes for the unequivocal detection and quantification of target proteins. Since fitting of the fluorescence decay for every pixel in an image using a classical exponential decay model is time-consuming and unstable at very low fluorescence intensities, we used a new, very robust and fast alternative method to generate UV fluorescence lifetime images by calculating the average lifetime of the decay for each pixel in the image stack using a model-free average decay time algorithm.To validate the method, we demonstrate the detection and quantification of p53 antibodies, a tumor marker in cancer diagnosis. Using tryptophan-containing capture peptides, we achieved a detection sensitivity for monoclonal antibodies down to the picomolar concentration range. The obtained affinity constant, Ka, of (1.4 +/- 0.6) x 10(9) M(-1), represents a typical value for antigen/antibody binding and is in agreement with values determined by traditional binding assays.
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PMID:UV fluorescence lifetime imaging microscopy: a label-free method for detection and quantification of protein interactions. 1644 37

The efficacy of anthracycline based anticancer drugs is limited by pleiotropic drug resistance of tumor cells. Aiming at the design of anthracyclinone congeners capable of circumventing drug resistance, we synthesized naphthoindole containing derivatives of tryptophan and tryptamine. In doing so we adapted the traditional, gramine based approach for tryptophan and tryptamine synthesis. The most potent new compound, 3-(2-aminoethyl)-4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione (16), was equally cytotoxic (IC(50) within low micromolar concentrations) for human K562 leukemia and HCT116 colon carcinoma cell lines and their isogenic sublines with genetically defined determinants of altered drug response, that is, the expression of the multidrug transporter P-glycoprotein and loss of pro-apoptotic p53. Each of these mechanisms conferred resistance to the reference drug adriamycin. In contrast, naphthotryptamine 16, although less potent than adriamycin, was equally toxic for wild type cell lines and drug resistant counterparts. Moreover, at 3-5 microM 16 inhibited topoisomerase I in vitro. Thus, our novel naphthoindole based derivative of tryptamine gained new activities important for anticancer therapy, namely, suppression of topoisomerase I and the ability to overcome resistance mediated by P-glycoprotein expression and p53 dysfunction.
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PMID:Naphthoindole-based analogues of tryptophan and tryptamine: synthesis and cytotoxic properties. 1727 90


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