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)

S100A2, a calcium binding protein of the EF-hand family, was recently identified to be inducible by etoposide, a p53 activator. A potential p53 binding site was identified in the promoter of the S100A2 gene, which binds to purified p53 as well as p53 in nuclear extract activated by etoposide. Transactivation assays using the promoter driven luciferase reporters revealed that the S100A2 promoter was transcriptionally activated by wild-type p53, but not by p53 mutants, in a dose-dependent as well as a p53 binding site-dependent manner. The p53-induced transactivation of the S100A2 promoter was enhanced by etoposide and blocked by a dominant negative p53 mutant. Furthermore, endogenous S100A2 mRNA expression is induced by etoposide in p53 positive, but not in p53 negative cells. Thus, p53 appears to positively regulate S100A2 expression.
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PMID:Transcriptional activation of the human S100A2 promoter by wild-type p53. 1009 69

DNA chip technology was used in an attempt to identify target genes responsible for apoptosis induced by etoposide, a p53 activating topoisomerase II inhibitor used clinically as an antitumor agent. 62 Individual mRNAs whose mass changed significantly were identified after screening oligonucleotide arrays capable of detecting 6591 unique human mRNA species. 12 (Nine induced and three repressed) of the etoposide-responsive genes were further studied by Northern analysis and an agreement rate of 92%, was reached. Among the 12 genes studied, two (WAF1/p21 and PCNA) are known p53 regulatory genes, two (glutathione peroxidase and S100A2 calcium-binding protein) appear to be the novel p53 target genes and the others appear to be p53-independent. Based upon these findings, the signalling pathways that possibly mediate etoposide-induced apoptosis are proposed.
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PMID:Identification of the genes responsive to etoposide-induced apoptosis: application of DNA chip technology. 1009 70

S100A2 is a calmodulin-like protein of unknown function, whose transcription is positively regulated in response to ErbB and p53 signaling. Expression of S100A2 is markedly increased in the context of ErbB-driven reactive epidermal hyperplasia, and decreased in the context of hypofunctional p53 mutations in carcinoma cell lines and tumors. This bimodal pattern of regulation suggests an important function for S100A2 in keratinocyte differentiation and carcinogenesis. Taking the biochemical approach to the determination of S100A2 function, we have characterized its physical state and subcellular localization in normal human keratinocytes. S100A2 in hypotonic lysates remained soluble after centrifugation at 100 000 x g, indicating that it is not associated with cell membranes. Permeabilization experiments confirmed the lack of membrane association and revealed a digitonin-insoluble nuclear fraction of S100A2, which was confirmed by immunofluorescence microscopy. Pulldown assays of epitope-tagged S100A2 and yeast two-hybrid screening revealed that S100A2 displays a strong propensity to homodimerize. Naturally expressed S100A2 dimers in normal human keratinocytes readily underwent intermolecular disulfide cross-linking unless a strong denaturant was present during cell lysis. Treatment of intact normal human keratinocytes with hydrogen peroxide strongly promoted S100A2 cross-linking. These results demonstrate that native S100A2 is a homodimer that does not depend on disulfide cross-linking for stability, but undergoes intermolecular cross-linking at cysteine residues in response to oxidative stress. Based on these findings, we propose that S100A2 may protect normal keratinocytes against carcinogens by participating in the cellular proof-reading response to oxidative stress.
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PMID:Biochemical characterization of S100A2 in human keratinocytes: subcellular localization, dimerization, and oxidative cross-linking. 1095 Dec 87

Apoptosis (programmed cell death) is a genetically programmed active cell death process for maintaining homeostasis under physiological conditions and for responding to various stimuli. Many human diseases have been associated with either increased apoptosis (such as AIDS and neurodegenerative disorders) or decreased apoptosis (such as cancer and autoimmune disorders). In an attempt to understand apoptosis signaling pathway and genes associated with apoptosis, we established two cell model systems on which apoptosis is induced either by DNA damaging agent, etoposide or by redox agent, 1,10-phenanthroline (OP). DNA chip profiling or mRNA differential display (DD) was utilized to identify genes responsive to apoptosis induced by these two agents. In etoposide model with chip hybridization, we defined signaling pathways that mediate apoptosis in p53 dependent manner (through activation of p53 target genes such as Waf-1/p21, PCNA, GPX, S100A2 and PTGF-beta) as well as in p53-independent manner (through activation of ODC and TGF-beta receptor, among others). In OP model with DD screening, we cloned and characterized two genes: glutathione synthetase, encoding an enzyme involved in glutathione synthesis and Sensitive to Apoptosis Gene (SAG), a novel evolutionarily conserved gene encoding a zinc RING finger protein. Both genes appear to protect cells from apoptosis induced by redox agents. Further characterization of SAG revealed that it is a growth essential gene in yeast and belongs to a newly identified gene family that promotes protein ubiquitination and degradation. Through this activity, SAG regulates cell cycle progression and many other key biological processes. Thus, SAG could be a valid drug target for anti-cancer and anti-inflammation therapies.
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PMID:Identification and characterization of genes responsive to apoptosis: application of DNA chip technology and mRNA differential display. 1100 51

S100A2 is a calmodulin-like, p53-inducible, homodimeric protein that is readily oxidized in keratinocytes subjected to oxidative stress. Here we compare the redox status and subcellular distribution of S100A2 in normal human keratinocytes, immortalized keratinocytes (HaCaT), and malignant keratinocytes (A431) as a function of oxidative stress and intracellular Ca2+ levels. Normal human keratinocytes displayed strong nuclear and moderate cytoplasmic S100A2 immunoreactivity. HaCaT and A431 cells, which lack normal p53, expressed S100A2 in similar patterns but in 4- to 8-fold lower amounts. H2O2 treatment of normal human keratinocytes caused a reduction of nuclear S100A2 staining accompanied by an increase in cytoplasmic S100A2 staining, with a delayed time course (0.5-1 h) relative to S100A2 oxidative crosslinking (15 min). This phenomenon, consistent with translocation of S100A2 from the nucleus to the cytoplasm, could also be induced in normal human keratinocytes by increasing intracellular Ca2+ levels with the ionophore A23187. Sulfhydryl reducing agents blocked these changes, whether induced by H2O2 or increased intracellular Ca2+ levels. A temporal correlation was identified between S100A2 translocation at 1 h and loss of cell viability at 24 h after H2O2 treatment. A431 and HaCaT cells were strongly resistant to H2O2-induced S100A2 crosslinking, S100A2 translocation, and cell death. Increased intracellular Ca2+ levels caused prominent translocation of S100A2 in normal human keratinocytes and HaCaT, but not in A431 cells. These results identify S100A2 oxidation and translocation as markers for early cellular responses to oxidative stress, which are markedly attenuated in immortalized and malignant keratinocytes.
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PMID:Differential responses of S100A2 to oxidative stress and increased intracellular calcium in normal, immortalized, and malignant human keratinocytes. 1244 12

Head and neck squamous cell carcinoma express high levels of the EF-hand calcium-binding protein S100A2 in contrast to other tumorigenic tissues and cell lines where the expression of this protein is reduced. Subtractive hybridization of tumorigenic versus normal tumor-derived mammary epithelial cells has previously identified the S100A2 protein as potential tumor suppressor. The biological function of S100A2 in carcinogenesis, however, has not been elucidated to date. Here, we report for the first time that during recovery from hydroxyurea treatment, the S100A2 protein translocated from the cytoplasm to the nucleus and co-localized with the tumor suppressor p53 in two different oral carcinoma cells (FADU and SCC-25). Co-immunoprecipitation experiments and electrophoretic mobility shift assay showed that the interaction between S100A2 and p53 is Ca(2+)-dependent. Preliminary characterization of this interaction indicated that the region in p53 involved with binding to S100A2 is located at the C terminus of p53. Finally, luciferase-coupled transactivation assays, where a p53-reporter construct was used, indicated that interaction with S100A2 increased p53 transcriptional activity. Our data suggest that in oral cancer cells the Ca(2+)- and cell cycle-dependent p53-S100A2 interaction might modulate proliferation.
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PMID:The calcium-binding protein S100A2 interacts with p53 and modulates its transcriptional activity. 1594 20

Previous studies suggest that some S100 proteins are involved in the progression of certain types of cancer. However, no comprehensive data is currently available on the expression of S100 family genes in lung adenocarcinomas. Oligonucleotide array, quantitative reverse transcription-polymerase chain reaction and western blot analyses of lung adenocarcinoma cell lines and bronchiolar epithelial cells (SAEC and NHBE) revealed that S100A2 and S100A4 were the most strikingly downregulated and upregulated members of the S100 family, respectively. Immunohistochemical analyses of 94 primary lung adenocarcinomas showed that positive S100A2 expression (33/94, 35.1%) was significantly associated with lymphatic invasion (P=0.0233) and positive S100A4 expression (19/94, 20.2%) with vascular invasion (P=0.0454). Interestingly, a strong inverse relationship was found between S100A4 and p53 expression (P=0.0008). Survival analyses showed that S100A4 positivity was associated with poor patient prognosis (P=0.042). S100A2 positivity was not associated with patient survival when the whole patient group was analyzed; however, S100A2 positivity was a favorable prognostic indicator in patients with p53-negative tumors (P=0.0448). Finally, we used oligonucleotide array analyses and identified potential S100A2 and S100A4 target genes involved in cancer progression: S100A2 induced RUNX3 and REPRIMO; S100A4 induced EZRIN, RUNX1 and WISP1; S100A2 repressed EGFR, NFKB2 and RELA2; and S100A4 repressed ANXA10 and IL1RN. Thus, the present study demonstrates involvement of S100A2 and S100A4 in the progression of lung adenocarcinomas and an inverse association between S100A4 and p53 expression, and provides a list of targets regulated by S100A2 and S100A4.
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PMID:Differential expression of S100A2 and S100A4 in lung adenocarcinomas: clinicopathological significance, relationship to p53 and identification of their target genes. 1636 3

The p53 paralogues p73, p63 and their respective truncated isoforms have been shown to be critical regulators of developmental and differentiation processes. Indeed, both p73- and p63-deficient mice exhibit severe developmental defects. Here, we show that S100A2 gene, whose transcript and protein are induced during keratinocyte differentiation of HaCaT cells, is a direct transcriptional target of p73beta and DeltaNp63alpha and is required for proper keratinocyte differentiation. Transactivation assays reveal that p73beta and DeltaNp63alpha exert opposite transcriptional effects on S100A2 gene. While DeltaNp63alpha is found in vivo onto S100A2 regulatory regions predominantly in proliferating cells, p73beta is recruited in differentiating cells. Silencing of p73 impairs the induction of S100A2 during the differentiation of HaCaT cells. Moreover, silencing of p73 or S100A2 impairs the proper expression of keratinocyte differentiation markers. Of note, p53 family members do not trigger S100A2 gene expression in response to apoptotic doses of cisplatin and doxorubicin.
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PMID:S100A2 gene is a direct transcriptional target of p53 homologues during keratinocyte differentiation. 1644 68

S100A2 is a Ca(2+)-binding EF-hand protein that is mainly localized in the nucleus. There, it acts as a tumour suppressor by binding and activating p53. Wild-type S100A2 and a S100A2 variant lacking cysteines have been purified. CD spectroscopy showed that there are no changes in secondary-structure composition. The S100A2 mutant was crystallized in a calcium-free form. The crystals, with dimensions 30 x 30 x 70 microm, diffract to 1.7 A and belong to space group P2(1)2(1)2(1), with unit-cell parameters a = 43.5, b = 57.8, c = 59.8 A, alpha = beta = gamma = 90 degrees. Preliminary analysis of the X-ray data indicates that there are two subunits per asymmetric unit.
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PMID:Purification and crystallization of the human EF-hand tumour suppressor protein S100A2. 1707 93

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


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