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)

In order to identify differentially expressed genes under growth conditions, quiescent vascular smooth muscle cells (VSMCs) were stimulated with foetal calf serum (FCS) or platelet-derived growth factor-BB (PDGF-BB) for different time periods. Analysing the gene expression by the differential display (DD) method, we identified the cDNA of the growth arrest and DNA damage inducible gene 45a (Gadd45a, also known as gadd45 and gadd45a). Treatment with FCS or PDGF-BB led to a transient down-regulating of Gadd45a expression during the G0/G1 phase and maximal expression when cells had completed division. We found that expression of p53 and BRCA1 mRNA precedes Gadd45a mRNA expression with a maximal induction in the S phase. As in smooth muscle cells, a similar pattern of the Gadd45a mRNA expression was observed in knockout Gadd45a(-/-) cultured mouse embryonic fibroblasts (MEFs). However, no differences between Gadd45a(+/+) and Gadd45a(-/-) cell lines were observed regarding their kinetics of cell division. These experiments suggest a function of Gadd45a when cells exit the cell cycle rather than when regulating the entry into the S phase.
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PMID:Regulation of Gadd45a mRNA expression in vascular smooth muscle under growth and stress conditions. 1158 14

Here we report the specific regulation of gadd45 expression in human melanoma cell lines following UVB radiation. This solar wavelength is likely to be involved in melanoma aetiology. We have previously shown that gadd45 expression is strongly enhanced in a p53-independent manner following UVB irradiation, unlike the other p53 target genes studied. Furthermore, gadd45 is specifically activated in melanocytes since its induction in response to UVB, is not observed in other skin cells such as keratinocytes or fibroblasts. To investigate this particular regulation of gadd45, we analysed the UVB-induced response of different gadd45 promoter regions. Thus, a minimal promoter region of 50 bp length, responsible for gadd45 activation in melanoma cell lines following UVB irradiation, was determined. In electrophoretic mobility shift assays (EMSAs), we showed that this region (-106/-56) of the gadd45 promoter which contains two identical octamers, binds the POU family gene products oct-1 and N-oct3. Given the specific expression pattern of N-oct3 in melanocyte, we invalidated the expression of this transcription factor in melanoma cells: such an abrogation of N-oct3 protein expression in melanoma cells impeded gadd45 UVB-response. Thus the response of melanocyte to UVB may use an original and previously undescribed pathway.
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PMID:The specific activation of gadd45 following UVB radiation requires the POU family gene product N-oct3 in human melanoma cells. 1170 67

Conformationally compromised oncogenic mutants of the tumor suppressor protein p53 can, in principle, be rescued by small molecules that bind the native, but not the denatured state. We describe a strategy for the rational search for such molecules. A nine-residue peptide, CDB3, which was derived from a p53 binding protein, binds to p53 core domain and stabilizes it in vitro. NMR studies showed that CDB3 bound to p53 at the edge of the DNA binding site, partly overlapping it. The fluorescein-labeled peptide, FL-CDB3, binds wild-type p53 core domain with a dissociation constant of 0.5 microM, and raises the apparent melting temperatures of wild-type and a representative oncogenic mutant, R249S core domain. gadd45 DNA competes with CDB3 and displaces it from its binding site. But this competition does not preclude CDB3 from being a lead compound. CDB3 may act as a "chaperone" that maintains existing or newly synthesized destabilized p53 mutants in a native conformation and then allows transfer to specific DNA, which binds more tightly. Indeed, CDB3 restored specific DNA binding activity to a highly destabilized mutant I195T to close to that of wild-type level.
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PMID:A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. 1178 40

C57BL/6 Trp53 heterozygous (N5) mice (p53+/- mice) show an increased sensitivity to tumorigenesis following exposure to genotoxic compounds and are being used as an alternate animal model for carcinogenicity testing. However, there is relatively little data regarding the effect of p53 heterozygosity on the genomic and cellular responses of target tissues in these mice to toxic insult, especially under chronic exposure conditions used in carcinogenicity bioassays. We hypothesized that heterozygosity at the p53 locus in p53+/- mice alters the expression of bone marrow p53-regulated genes involved in cell cycle control and apoptosis during chronic genotoxic stress. We used real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) to examine gene expression alterations in bone marrow cells from C57BL/6 p53+/+ and isogenic p53+/- mice chronically exposed for 15 weeks to genotoxic and carcinogenic levels (100 ppm) of inhaled benzene. Examination of mRNA levels of p53-regulated genes involved in cell cycle control (p21, gadd45, and cyclin G) or apoptosis (bax and bcl-2) showed that during chronic genotoxic stress, bone marrow cells from p53+/+ mice expressed significantly higher levels of a majority of these genes compared to p53+/- bone marrow cells. Our results indicate that p53 heterozygosity results in a haploinsufficient phenotype in p53+/- bone marrow cells as evident by significantly altered mRNA levels of key genes involved in the p53-regulated DNA damage response pathway.
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PMID:p53 heterozygosity alters the mRNA expression of p53 target genes in the bone marrow in response to inhaled benzene. 1189 87

Studies reported here tested the hypothesis that acetaminophen stimulates proliferation of E2-responsive cells by inducing expression of E2-regulated genes. Ribonuclease protection assays compared the effects of acetaminophen and E2 on expression of selected genes (c-myc, c-fos, cyclin D1, bcl-2, bax, gadd45, mcl-1, p53, p21(CIP1/WAF1), and bcl-xL) in E2-responsive breast cancer (MCF-7) and endometrial adenocarcinoma (Ishikawa) cells as well as in E2-nonresponsive (MDA-MB-231) breast cancer cells. Acetaminophen and E2 increased c-myc RNA levels in MCF-7 cells, consistent with a mitogenic activity of these compounds in MCF-7 cells. However, the magnitude and time course of acetaminophen and E2 induction of c-myc differed. Neither acetaminophen nor E2 induced c-myc in MDA-MB-231 cells, whereas E2, but not acetaminophen, weakly induced c-myc expression in Ishikawa cells. Furthermore, in these 3 cell types, the expression patterns of the other genes differed dramatically in response to acetaminophen and to E2, indicating that acetaminophen does not activate ER as a transcription factor in the same manner as does E2. Additionally, gel shift assays demonstrated that in MCF-7 cells, acetaminophen increased NF-kappaB activity approximately 40% and did not alter AP-1 activity, whereas E2 increased AP-1 activity approximately 50% and did not increase NF-B activity. These studies indicate that acetaminophen effects on gene expression and cell proliferation depend more on cell type/context than on the presence of ER.
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PMID:Acetaminophen-induced proliferation of estrogen-responsive breast cancer cells is associated with increases in c-myc RNA expression and NF-kappaB activity. 1189 90

The purpose of our study was to analyze the p53-mediated response of human melanocytes and human melanoma cells to UVB (natural environmental carcinogen) or UVC irradiation (experimental carcinogen). A semi-quantitative RT-PCR method was developed to allow the analysis of the expression of 5 p53 effector genes (p21(WAF1), mdm2, cyclin G1, gadd45, bax) at the same time with a small amount of RNA (1 microg). In human melanocytic cells, the p53 downstream genes were found to be differentially activated after UVB and UVC irradiation. After UVB irradiation, p53 protein accumulation was sustained up to 48 hr that was not the case after UVC irradiation. Among the p53 effector genes tested, gadd45 was the only 1 to show a strong and specific induction after UVB irradiation. With high UVB doses, gadd45 was also the only gene to be transcribed. By contrast, after UVC irradiation, all the p53 effector genes tested were transcriptionally induced. Experiments conducted with fibroblasts and keratinocytes didn't show such a striking activation of gadd45 after UVB irradiation. These results point out the potential role of gadd45 in response to UVB irradiation in human melanocytes and the different p53-mediated responses to different carcinogens.
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PMID:Specific induction of gadd45 in human melanocytes and melanoma cells after UVB irradiation. 1194 56

Prostaglandin D(2) (PGD(2)), a major cyclooxygenase product in a variety of tissues and cells, readily undergoes dehydration to yield the bioactive cyclopentenone-type PGs of the J(2)-series, such as 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)). The observation that the level of 15d-PGJ(2) increased in the tissue cells from patients with sporadic amyotrophic lateral sclerosis suggested that the formation of 15d-PGJ(2) may be closely associated with neuronal cell death during chronic inflammatory processes. In vitro experiments using SH-SY5Y human neuroblastoma cells revealed that 15d-PGJ(2) induced apoptotic cell death. An oligonucleotide microarray analysis demonstrated that, in addition to the heat shock-responsive and redox-responsive genes, the p53-responsive genes, such as gadd45, cyclin G1, and cathepsin D, were significantly up-regulated in the cells treated with 15d-PGJ(2). Indeed, the 15d-PGJ(2) induced accumulation and phosphorylation of p53, which was accompanied by a preferential redistribution of the p53 protein in the nuclei of the cells and by a time-dependent increase in p53 DNA binding activity, suggesting that p53 accumulated in response to the treatment with 15d-PGJ(2) was functional. The 15d-PGJ(2)-induced accumulation of p53 resulted in the activation of a death-inducing caspase cascade mediated by Fas and the Fas ligand.
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PMID:15-Deoxy-Delta(12,14)-prostaglandin J(2): the endogenous electrophile that induces neuronal apoptosis. 1203 89

Although it is clear that p53 plays a pivotal role in G1/G2 checkpoints to conserve genomic integrity, its role in S phase checkpoint is less well understood. Recently, it has been reported that p53 is transcriptionally impaired even though it is stabilized during replication blockade. However, the mechanisms underlying this phenomenon are not known. In the present study, it has been shown that p53 accumulates and transactivates its target genes such as p21, gadd45 and bax in response to replication blockade in normal and cancer cells. Lack of transcriptional activation under similar conditions in cells lacking p53 shows that p53-target gene activation during replication blockade is indeed p53-dependent. Further, transactivation of p21 in response to replication blockade by hydroxyurea and aphidicolin is similar to that in response to ionizing radiation except that the latter is more immediate compared to the response to replication blockade. These findings suggest that impairment of transcriptionally active p53 in response to replication blockade is not a general phenomenon.
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PMID:Stabilization of p53 and transactivation of its target genes in response to replication blockade. 1237 Aug 12

Previous work from our laboratory has suggested the functional contribution of p53 to the cascade of events triggered by excitatory amino acids and leading to cell death in primary neurons. Here we show that this paradigm can be extended to cortical neurons treated with NMDA. We found that exposure of the cells to either 300 microM or 2 mM NMDA induced an enhancement of p53 protein levels which was already significant at 60 min after the lesion, while very low staining of the protein was observed in untreated cells. The effect was time- and concentration-dependent, reaching the maximal induction at 3 h. NMDA treatment also resulted in an increase of gadd45 protein levels which was evident in both treatment at 3 h, the time when p53 was maximally induced. Our data give further evidence suggesting that a repertoire of events typical of proliferating cells is activated in degenerating neurons.
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PMID:Expression of cell-cycle-related proteins and excitoxicity. 1237 14

Mechanisms of 5-azacytidine (5AzC)-induced toxicity in the rat foetal brain were investigated. 5AzC (10 mg/kg) was injected into pregnant rats on day 13 of gestation and the protein and mRNA expressions of p53 and its transcriptional target genes, p21, bax, cyclin G1, fas, and gadd45, were examined in the foetal brain. The number of p53-positive cells peaked at 9 h after treatment (HAT) and those of apoptotic cells and p21-positive cells peaked at 12 HAT. The expressions of p21, bax, cyclin G1, and fas mRNAs were significantly elevated from 9 to 12 HAT. From the experiments using 5-bromo-2'-deoxyuridine (BrdU), as compared with controls, the migration of neuroepithelial cells significantly delayed and BrdU-positive signals were observed in many apoptotic cells from 9 to 24 HAT in the 5AzC-group. In addition, the number of S phase cells significantly decreased at 12 HAT. The present results indicate that 5AzC induced apoptosis and cell cycle arrest probably at G1 phase in the rat foetal brain and they might be mediated by p53 in response to DNA damage.
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PMID:Mechanisms of 5-azacytidine (5AzC)-induced toxicity in the rat foetal brain. 1238 93


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