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)

Gene expression patterns in ductal carcinoma in situ (DCIS) and invasive and metastatic breast tumors have been determined using serial analysis of gene expression (SAGE). The purpose of this approach was to identify biologically and clinically meaningful subgroups of DCIS with a high risk of progression to invasive disease. The analyses have led to the identification of several differentially expressed genes, such as HIN-1, dermcidin and S100A7 (psoriasin). The aim of the present study was further to delineate the expression profile of S100 genes using information from 22 breast epithelial SAGE libraries. We demonstrated the down-regulation of S100A6 and S100A10 in breast cancer, irrespective of pathological stage. S100P and S100Z were both up-regulated in cancer; whereas S100A7, S100A8 and S100A9 were strongly up-regulated only in DCIS. The hierarchical clustering of S100 gene expression in these 22 libraries revealed two major groups with distinguishable S100 gene expression profiles. One of them was characterized by the high concomitant expression of S100A7, S100A8 and S100A9. Using SAGE informatics, we found 21 genes with a high positive correlation to S100A7 expression in libraries representing different categories of tissues archived at SAGE Genie, suggesting a function of psoriasin that is not tissue specific. Like S100A7, several of these genes displayed cation-binding properties. We also report the strong correlation in the breast epithelial SAGE libraries between the expression of S100A7 and genes reported as being up-regulated in DCIS, as well as in the inflammatory skin disorder, psoriasis; including RGS5, UPK1A, TMPRSS3, S100A9, p53, SCCA1, SCCA2 and KRT17.
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PMID:Cluster analysis of S100 gene expression and genes correlating to psoriasin (S100A7) expression at different stages of breast cancer development. 1627 1

Early and correct diagnosis of non-small cell lung carcinoma (NSCLC) is essential for the choice of an appropriate anti-cancer therapy. Besides the histopathological diagnosis, molecular profiling by detection of the tumour-associated gene expression might play an upcoming role. As proteins of the S100 gene family show a distinct cell type-specific expression profile, our study focused on the relevance of the S100 family for identification and classification of NSCLCs. Among the S100 members, we identified the expression of S100A1, S100A2, S100A4, S100A6, S100A9 and S100P in human lung carcinoma cells (H358(p53-), A549(p53+)) or NSCLC tissues. Distinct S100 members are increased in NSCLCs compared with control lung specimens depending on the histopathological subtype. In particular, S100A2 was upregulated in squamous cell carcinomas, whereas S100P was mainly increased in adenocarcinomas. The upregulation of either S100A2 or S100P was detected in early but less in advanced tumour stages and not at all in NSCLC patients who had received neoadjuvant chemotherapy. In conclusion, our study indicates an important role of the S100A2-S100P expression profile for molecular diagnosis of NSCLCs at early and, therefore, prognostically more favourable tumour stage. As the S100A2-S100P profile also allows the histopathological classification, it might significantly support the conventional tumour diagnostics.
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PMID:S100A2-S100P expression profile and diagnosis of non-small cell lung carcinoma: impairment by advanced tumour stages and neoadjuvant chemotherapy. 1768 67

The cellular response to genotoxic stress is a complex cascade of events including altered protein expression, interactions, modifications, and relocalization, leading to cell cycle arrest and DNA repair or to apoptosis. p53 protein has a central role in this process, and p53 status is an important factor in the response of a tumor to genotoxic anticancer therapy. We studied p53-related changes postexposure to ionizing radiation using top-down mass spectrometry. Initially two cell lines were compared, HCT116 p53 wild type (wt) and p53(-/-), in a time course study postirradiation. In the p53 wt cell line a striking increase of a 10.2-kDa protein was detected, and this protein was identified with MS/MS analysis as S100A6. Further MS profiling led to detection of two post-translationally modified variants of S100A6, namely glutathionylated and cysteinylated forms. In p53 wt cells, a specific shift from glutathionylated to cysteinylated S100A6 occurred postirradiation. The p53 dependence of this specific change in protein level and modification pattern of S100A6 postirradiation was confirmed in a panel of four lung cancer cell lines (H23, U1810, H69, and A549) with different p53 status and using small interfering RNA against p53. Interestingly the closely related S100 family protein S100A4 showed the same changes in modification pattern post-ionizing radiation in the p53 wt lung cancer cell line, and S100A4 also showed p53-dependent expression. Using confocal microscopy, relocalization of S100A6 from nucleus to cytosol and a colocalization with tropomyosin in stress fibers was detected in A549 cells postirradiation. This relocalization coincided with the change in S100A6 modification pattern. Based on these results, we suggest that S100A6 and S100A4 are regulated via redox modifications in vivo and that these proteins are involved in the cellular response to genotoxic stress.
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PMID:Up-regulation, modification, and translocation of S100A6 induced by exposure to ionizing radiation revealed by proteomics profiling. 1778 50

S100A2 is an EF hand-containing Ca(2+)-binding protein of the family of S100 proteins. The protein is localized exclusively in the nucleus and is involved in cell cycle regulation. It attracted most interest by its function as a tumor suppressor via p53 interaction. We determined the crystal structure of homodimeric S100A2 in the Ca(2+)-free state at 1.6-A resolution. The structure revealed structural differences between subunits A and B, especially in the conformation of a loop that connects the N- and C-terminal EF hands and represents a part of the target-binding site in S100 proteins. Analysis of the hydrogen bonding network and molecular dynamics calculations indicate that one of the two observed conformations is more stable. The structure revealed Na(+) bound to each N-terminal EF hand of both subunits coordinated by oxygen atoms of the backbone carbonyl and water molecules. Comparison with the structures of Ca(2+)-free S100A3 and S100A6 suggests that Na(+) might occupy the S100-specific EF hand in the Ca(2+)-free state.
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PMID:Crystal structure of Ca2+ -free S100A2 at 1.6-A resolution. 1839 45

p53 binds to some members of the S100 family (S100B, S100A4, S100A2, and S100A1). We previously showed that both S100B and S100A4 bind to the p53 tetramerization domain, and consequently control its oligomerization state, but only S100B binds to the C-terminal negative regulatory domain (NRD). Here, we investigate other binding partners for p53 within the S100 family (S100A6 and S100A11), and show that binding to the p53 tetramerization domain seems to be a general feature of the S100 family, while binding to the NRD is a characteristic of a subset of the family.
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PMID:Members of the S100 family bind p53 in two distinct ways. 1869 25

Calcyclin (S100A6) is believed to participate in cell cycle control. It was, however, unclear if its expression depends on p53, a key regulator of apoptosis and cell cycle. We therefore performed transcription regulation assays in HeLa cells and found that wild type p53 suppressed the S100A6 promoter up to 12-fold in a dose-dependent manner. In contrast, the well-characterized V143A, R175H, R249S, and L344A p53 mutants cloned from human cancers suppressed this promoter with a 6 to 9-fold lower efficiency. All the sites mediating the p53-dependent suppression were contained in the -167 to +134 fragment of the S100A6 promoter. Separate overexpression of either Sp1 or of NFkappaB only partially counteracted the p53 inhibitory effect on the S100A6 promoter, while simultaneous overexpression of both these transactivators resulted in a complete abolishment of the p53 inhibitory effect on this promoter. Sp1 and NFkappaB binding to the probes resembling their putative binding sites present in the S100A6 promoter was decreased in the presence of wild type p53. We propose that the suppression of S100A6 is yet another mechanism by which p53 inhibits proliferation. Insufficient suppression of this gene by p53 mutants could well be responsible for calcyclin overexpression and cell cycle deregulation observed in cancer tissues.
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PMID:P53-dependent suppression of the human calcyclin gene (S100A6): the role of Sp1 and of NFkappaB. 1871 2

S100A6 is induced in myocardium post-infarction in vivo and in response to growth factors and inflammatory cytokines in vitro. Forced expression of S100A6 in cardiomyocytes inhibits regulation of cardiac specific gene expression in response to trophic stimulation. To define regulation and function of S100A6, we characterized the human S100A6 promoter and mapped upstream regulatory elements in rat neonatal cardiac myocytes, fibroblasts, and vascular smooth muscle cells and defined a functional role for S100A6 in tumor necrosis factor-alpha-induced myocyte apoptosis. The functional S100A6 promoter was localized to region -167/+134 containing 167 upstream base pairs. The S100A6 promoter is regulated by positive (-361/-167 and -588/-361) and negative (-1371/-1194) elements. Tumor necrosis factor-alpha induced the maximal S100A6 promoter and transcription factor NF-kappaB (p65 subunit). Electrophoretic mobility shift showed that tumor necrosis factor-alpha induced p65 binding to a potential NF-kappaB-binding site at -460/-451. Chromatin immunoprecipitation analysis revealed p65 is recruited to the S100A6 promoter upon tumor necrosis factor-alpha stimulation. The NF-kappaB inhibitor caffeic acid phenethyl ester and mutation of the NF-kappaB-binding site inhibited S100A6 promoter activation by tumor necrosis factor-alpha. Tumor necrosis factor-alpha induced cardiac myocyte apoptosis. Specific inhibition of S100A6 using a small interfering RNA directed against S100A6 potentiated tumor necrosis factor-alpha-induced myocyte apoptosis, whereas overexpression of S100A6 by gene transfer prevented tumor necrosis factor-alpha-induced myocyte apoptosis by interfering with p53 phosphorylation. These results demonstrate that S100A6 is induced by tumor necrosis factor-alpha via an NF-kappaB-dependent mechanism, serving a role in homeostasis to limit tumor necrosis factor-alpha-induced apoptosis by regulating p53 phosphorylation.
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PMID:Expression of S100A6 in cardiac myocytes limits apoptosis induced by tumor necrosis factor-alpha. 1875 41

S100A6 (calcyclin) is a calcium-binding protein implicated in many cellular processes and often up-regulated in cancer. Its various biological effects possibly originate from the fact that it may bind to other proteins and modulate their function by inducing conformational changes or interfering with posttranslational modifications. Thus, to elucidate the biological role of S100A6 it is important to identify its targets. Here, we report, based on affinity chromatography and co-immunoprecipitation results that S100A6 interacts with p53 in the presence of calcium ions. We investigated functional implications of the S100A6-p53 interaction by comparing various aspects of p53 activity in HEp-2 cells with either unaltered or diminished S100A6 content due to stable expression of siRNA. We found that the presence of S100A6 results in higher p53 transcriptional activity which is also reflected by higher cell susceptibility to apoptosis evoked by hydrogen peroxide. As revealed by electrophoretic mobility shift assay (EMSA) S100A6 does not affect p53 binding to DNA. On the other hand, we observed that the presence of S100A6 coincides with more efficient nuclear accumulation of p53 under stress conditions. Collectively, our results indicate that S100A6 interacts with p53 and affects its biological activity.
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PMID:S100A6 binds p53 and affects its activity. 1876 92

We investigated the ways S100B, S100A1, S100A2, S100A4, and S100A6 bind to the different oligomeric forms of the tumor suppressor p53 in vitro, using analytical ultracentrifugation and multiangle light scattering. It is established that members of the S100 protein family bind to the tetramerization domain (residues 325-355) of p53 when it is uncovered in the monomer, and so binding can disrupt the tetramer. We found a stoichiometry of one dimer of S100 bound to a monomer of p53. We discovered that some S100 proteins could also bind to the tetramer. S100B bound the tetramer and also disrupted the dimer by binding monomeric p53. S100A2 bound monomeric p53 as well as tetrameric, whereas S100A1 only bound monomeric p53. S100A6 bound more tightly to tetrameric than to monomeric p53. We also identified an additional binding site for S100 proteins in the transactivation domain (1-57) of p53. Based on our results and published observations in vivo, we propose a model for the binding of S100 proteins to p53 that can explain both activation and inhibition of p53-mediated transcription. Depending on the concentration of p53 and the member of the S100 family, binding can alter the balance between monomer and tetramer in either direction.
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PMID:Modulation of the oligomerization state of p53 by differential binding of proteins of the S100 family to p53 monomers and tetramers. 1929 17

Proteins of the S100 family bind to the intrinsically disordered transactivation domain (TAD; residues 1-57) and C-terminus (residues 293-393) of the tumor suppressor p53. Both regions provide sites that are subject to posttranslational modifications, such as phosphorylation and acetylation, that can alter the affinity for interacting proteins such as p300 and MDM2. Here, we found that S100A1, S100A2, S100A4, S100A6, and S100B bound to two subdomains of the TAD (TAD1 and TAD2). Both subdomains were mandatory for high-affinity binding to S100 proteins. Phosphorylation of Ser and Thr residues increased the affinity for the p53 TAD. Conversely, acetylation and phosphorylation of the C-terminus of p53 decreased the affinity for S100A2 and S100B. In contrast, we found that nitrosylation of S100B caused a minor increase in binding to the p53 C-terminus, whereas binding to the TAD remained unaffected. As activation of p53 is usually accompanied by phosphorylation and acetylation at several sites, our results suggest that a shift in binding from the C-terminus in favor of the N-terminus occurs upon the modification of p53. We propose that binding to the p53 TAD might be involved in the stimulation of p53 activity by S100 proteins.
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PMID:Posttranslational modifications affect the interaction of S100 proteins with tumor suppressor p53. 1981 44


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