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

Okadaic acid, a phosphatase inhibitor from a marine organism, mimics tumor necrosis factor/interleukin-1 (TNF/IL-1) in inducing changes in early cellular protein phosphorylation. A total of approximately 116 proteins exhibit significant and concordant changes in phosphorylation or dephosphorylation within 15 min in human fibroblasts activated by either okadaic acid, TNF, or IL-1. The fidelity of this mimicry by okadaic acid extends to the phosphorylation of the 27 hsp complex, stathmin, eIF-4E, myosin light chain, nucleolin, epidermal growth factor receptor, and other cdc2-kinase substrates (c-abl, RB, and p53). The okadaic acid-induced pattern of protein phosphorylation is distinct from that observed in cells treated with phorbol 12-myristate 13-acetate or with ligands like epidermal growth factor, cyclic AMP agonists, bradykinin, or interferons. Like TNF, okadaic acid also induces the transcription of immediate early response genes like c-jun and Egr-1 as well as the interleukin-6 genes. The overall early effects of okadaic acid uniquely parallel those of TNF/IL-1 and not those of other cytokines or ligands. Regulation of protein phosphatase inhibition is discussed as a mechanism for TNF/IL-1 signal transduction.
 ...
PMID:Okadaic acid mimics multiple changes in early protein phosphorylation and gene expression induced by tumor necrosis factor or interleukin-1. 137 Apr 82

The tumor suppressor molecule p53 features a regulatory domain at the C terminus that recognizes damaged DNA. Since damaged DNA might be involved in activating anti-DNA autoantibodies, we tested whether autoimmunity to the C terminus of p53 might mark murine systemic lupus erythematosus (SLE). We now report that MRL / MpJ-Fas(lpr) mice, which spontaneously develop SLE, produce antibodies both to the C terminus of p53 and to a monoclonal antibody (PAb-421) that binds the p53 C terminus. Anti-idiotypic antibodies to PAb-421 (sampled as monoclonal antibodies) could also bind DNA. Thus, the PAb-421 antibody mimics DNA, and the anti-idiotypic antibody to PAb-421 mimics the p53 DNA-binding site. This mimicry was functional; immunization of BALB / c mice to PAb-421 induced anti-DNA antibodies and antibodies to the C terminus of p53, and most of the mice developed an SLE-like disease. Immunization of C57BL / 6 mice to PAb-421 induced antibodies to p53, but not to its C-terminal domain. The C57BL / 6 mice also did not develop anti-DNA antibodies or the SLE-like disease. Thus, network autoimmunity to the domain of p53 that recognizes damaged DNA can be a pathogenic feature in SLE in genetically susceptible strains of mice.
 ...
PMID:Systemic lupus erythematosus in mice, spontaneous and induced, is associated with autoimmunity to the C-terminal domain of p53 that recognizes damaged DNA. 1076 Jul 84

Werner syndrome (WS) is an autosomal recessive disease manifested by the premature onset of age-related phenotypes, including diseases such as atherosclerosis and cancer. This mimicry of normal aging with the possible exception of central nervous system manifestations has made it a focus of recent molecular studies on the pathophysiology of aging. In culture, cells obtained from patients with WS are genetically unstable, characterized by an increased frequency of nonclonal translocations and extensive DNA deletions. The WS gene product (WRN) is a DNA helicase belonging to the RecQ family, but is unique within this family in that it also contains an exonuclease activity. In addition to unwinding double-stranded DNA, WRN helicase is able to resolve aberrant DNA structures such as G4 tetraplexes, triplexes and 4-way junctions. Concordant with this structure-specificity, WRN exonuclease preferentially hydrolyzes alternative DNA that contains bubbles, extra-helical loops, 3-way junctions or 4-way junctions. WRN has been shown to bind to and/or functionally interact with other proteins, including replication protein A (RPA), proliferating cell nuclear antigen (PCNA), DNA topoisomerase I, Ku 86/70, DNA polymerase delta and p53. Each of these interacting proteins is involved in DNA transactions including those that resolve alternative DNA structures or repair DNA damage. The biochemical activities of WRN and the functions of WRN associated proteins suggest that in vivo WRN resolves DNA topological or structural aberrations that either occur during DNA metabolic processes such as recombination, replication and repair, or are the outcome of DNA damage.
 ...
PMID:Unwinding the molecular basis of the Werner syndrome. 1134 59

The induction of anti-DNA autoantibodies in systemic lupus erythematosus (SLE) patients is problematic because mammalian DNA is poorly immunogenic at best. Here we demonstrate a chain of connected antibodies in SLE patient sera that could account for the induction of anti-DNA antibody, and possibly for some of the pathogenic features of SLE. We now report that SLE patients, in addition to anti-DNA, produce antibodies to the carboxy-terminal domain of the tumour suppressor molecule p53; this p53 domain recognizes damaged DNA. Hence, these anti-p53 antibodies could mimic damaged DNA immunologically. Indeed, SLE sera do contain anti-idiotypic antibodies to a prototypic anti-p53 antibody. Moreover, SLE anti-DNA antibodies also recognize this type of anti-p53 antibody. Indeed, binding of affinity-purified anti-DNA both to DNA and to the anti-p53 antibody could be blocked by a p53 peptide derived from the DNA-binding domain. This mimicry of the p53 DNA-binding domain by the SLE anti-DNA antibodies is functional: activation of the p53 molecule could be inhibited by such anti-DNA antibodies. Thus, anti-DNA antibodies may arise in SLE patients by a chain of idiotypic autoimmunity centered around p53 autoimmunity. The SLE anti-DNA and anti-p53 antibodies can functionally block p53 activation, and so could affect apoptosis.
 ...
PMID:Autoimmunity to the p53 protein is a feature of systemic lupus erythematosus (SLE) related to anti-DNA antibodies. 1148 38

An N-terminal helical region of the tumor suppressor p53 binds in a hydrophobic cleft of the oncoprotein MDM2. A retroinverso isomer of the natural N-terminal helical peptide was found to interact with MDM2 using the same hydrophobic residues, Phe, Trp, and Leu. We propose that the retroinverso d-peptide adopts a right-handed helical conformation to achieve functional mimicry of the p53 peptide.
 ...
PMID:Use of a retroinverso p53 peptide as an inhibitor of MDM2. 1560 Mar 7

We recently reported a beta-peptide foldamer, beta53-1, that folds into a 14-helix in aqueous solution, binds the oncoprotein hDM2 with submicromolar affinity, and potently inhibits the interaction of hDM2 with a peptide derived from the activation domain of p53 (p53AD). Here, we present the solution structure of beta53-1 in methanol. Details of the structure illustrate fundamental and novel elements of beta-peptide folding and recognition. These elements include the detailed arrangement of a complex, 14-helix-stabilizing salt bridge on one helical face, and a unique "wedge into cleft" packing interaction along a second. The structure also reveals how a subtle distortion in the beta53-1 14-helix geometry alters the presentation of its recognition epitope, rendering it particularly well suited for alpha-helix mimicry. The solution structure of beta53-1 demonstrates that well folded beta-peptide oligomers can effectively present an extended, highly variable surface that could be used as a general platform for targeting critical protein-protein interfaces.
 ...
PMID:Solution structure of a beta-peptide ligand for hDM2. 1578 63

We describe a general method for the mimicry of one face of an alpha-helix based on a terphenyl scaffold that spatially projects functionality in a manner similar to that of two turns of an alpha-helix. The synthetic scaffold reduces the flexibility and molecular weight of the mimicked protein secondary structure. We have applied this design to the development of antagonists of the alpha-helix binding protein Bcl-x(L). Using a sequential synthetic strategy, we have prepared a library of terphenyl derivatives to mimic the helical region of the Bak BH3 domain that binds Bcl-x(L). Fluorescence polarization assays were carried out to evaluate the ability of terphenyl derivatives to displace the Bcl-x(L)-bound Bak peptide. Terphenyl 14 exhibited good in vitro affinity with a K(i) value of 0.114 muM. These terphenyl derivatives were more selective at disrupting the Bcl-x(L)/Bak over the HDM2/p53 interaction, which involves binding of the N-terminal alpha-helix of p53 to HDM2. Structural studies using NMR spectroscopy and computer-aided docking simulations suggested that the helix binding area on the surface of Bcl-x(L) is the target for the synthetic ligands. Treatment of human embryonic kidney 293 (HEK293) cells with terphenyl derivatives resulted in the disruption of the binding of Bcl-x(L) to Bax in intact cells.
 ...
PMID:Terphenyl-Based Bak BH3 alpha-helical proteomimetics as low-molecular-weight antagonists of Bcl-xL. 1602 29

This tutorial focuses on salivary duct carcinoma (SDC), a rare, high grade neoplasm mainly of major salivary glands. The clinical course of these tumors is characterised by extended local disease, early distant metastasis, and poor outcome. The morphology of SDC is reminiscent of breast ductal carcinomas and may occasionally cause diagnostic problems. In spite of mimicry with ductal carcinoma in situ of the breast and an in situ component, that is evident in most tumors by immunohistology with antibodies directed against high molecular weight cytokeratins (Ck), SDC is always an invasive carcinoma. By immunohistology, most tumors show reactivity with antibodies directed against Ck 7, Ck 8/18 and Ck 19 whereas a morphologically indistinguishable subgroup expresses Ck 5/6 in tumor cells in addition to residual basal epithelia. Carcinoembryonic antigen, GCDFP-15 and androgen receptor are other helpful markers in routine diagnosis of SDC. Prostate-specific antigen is detectable in some cases. Abnormal p53 expression seems to indicate an adverse prognosis. Expression of c-erbB2, the over-expression of which is associated with a poor prognosis, may form the basis for a targeted therapeutic approach for selected cases of SDC.
 ...
PMID:[Salivary duct carcinoma]. 1604 4

Inhibitors for the classical protein deacetylase enzymes have been actively pursued to develop the next generation of cancer therapy. Developing a novel convenient assay platform for the classical enzyme-catalyzed reactions could thus facilitate the drug discovery process. Based on our previous studies demonstrating the functional mimicry of N(epsilon)-thioacetyl-lysine for N(epsilon)-acetyl-lysine in the reaction catalyzed by the classical enzyme histone deacetylase 8 (HDAC8) on a peptide template derived from the C terminus of the human p53 tumor suppressor protein, we have developed a spectrophotometric HDAC8 assay via quantifying thioacetate produced from the enzymatic dethioacetylation with Ellman's reagent 5,5'-dithiobis(2-nitrobenzoate). We further demonstrated that this novel assay was selective for HDAC8 versus HDAC1 and 2 and for other classical protein deacetylase enzymes present in the HeLa nuclear extracts, thus making it potentially suitable not only for screening HDAC8-selective inhibitors but also for selectively assessing HDAC8 activity under (patho)physiological conditions.
 ...
PMID:A spectrophotometric assay for histone deacetylase 8. 1792 May 54

The inhibition of protein-protein interactions using small molecules is a viable approach for the treatment of a range of pathological conditions that result from a malfunctioning of these interactions. Our strategy for the design of such agents involves the mimicry of side-chain residues on one face of the alpha-helix; these residues frequently play a key role in mediating protein-protein interactions. The first-generation terphenyl scaffold, with a 3,2',2''-substitution pattern, is able to successfully mimic key helix residues and disrupt therapeutically relevant interactions, including the Bcl-X(L)-Bak and the p53-hDM2 (human double minute 2) interactions that are implicated in cancer. The second- and third-generation scaffolds have resulted in greater synthetic accessibility and more drug-like character in these molecules.
 ...
PMID:alpha-Helix mimetics as inhibitors of protein-protein interactions. 1902 66


1 2 3 4 Next >>