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)

Poly(ADP-ribose) polymerase-1 (PARP-1, EC 2.4.2.30), a DNA-bound enzyme, plays a key role in genome stability, but after overactivation can also be responsible for cell death. The aim of the present study was to investigate PARP-1 activity in the hippocampus, brain cortex, striatum and cerebellum in adult (4 months) and aged (24 months) specific pathogen free Wistar rats and to correlate it with PARP-1 protein level and p53 expression. Moreover, the response of PARP-1 in adult and aged hippocampus to oxidative/genotoxic stress was evaluated. Our data indicated a statistically significant enhancement of PARP-1 activity in aged hippocampus and cerebral cortex comparing to adults without statistically significant changes in PARP-1 protein level. The expression of p53 mRNA was elevated in all aged brain parts with the exception of the cerebral cortex. Our data suggest that enhancement of PARP-1 activity and p53 expression in aged brain may indicate higher DNA damage. Our data also indicate that during excessive oxidative/genotoxic stress there is no response of PARP-1 activity in aged hippocampus in contrast to a significant enhancement of PARP-1 activity in adults which may have important consequences for the physiology and pathology of the brain.
Acta Biochim Pol 2005
PMID:Effect of aging and oxidative/genotoxic stress on poly(ADP-ribose) polymerase-1 activity in rat brain. 1630 26

According to classic theory of neogenesis, cancer arises from well-differentiated cell that in response to variety of factors de-differentiates, becomes able to proliferate without control and/or loses its ability to undergo apoptosis. According to another theory, cancers (at least cancers of some organs) originate from stem cells, which "by definition" are poorly differentiated and able to proliferate indefinitely. Therefore a lower number of abnormal events is necessary for these cells to escape proliferation-controlling mechanisms. With regard to papillary thyroid cancers it is still thought that it arises from well-differentiated thyreocyte. One of the characteristic features of cancer cell is chromosomal instability. Lowest number of such abnormalities is observed in well-differentiated thyroid cancers (including papillary cancer), intermediate - in poorly-differentiated cancers, while highest - in anaplastic cancers. Microarray analysis shows that despite of clinical heterogeneity, gene expression profiles of papillary cancers are very similar. Genetic anomalies predisposing to the development of papillary cancer most commonly regard proteins that possess kinase activity. Kinases phosphorylate other proteins, and play an extremely important role in signal transduction from outside the cell as well as inside the cell. Constitutive activation of some kinases may lead to the excessive and/or permanent activation of some transduction pathways specific for mitogens or growth factors. This results in excessive proliferation. The best known protein of such type which function is altered in papillary thyroid cancers is RET - a membrane-located growth factor-receptor with kinase activity. RET gene undergoes different rearrangements in this type of cancer. There are approximately 10 RET rearrangements known, with RET/PTC3 and RET/PTC1 being most common. In this anomaly kinase domain-encoding 3' end of RET gene is aberrantly bound to 5' end of another gene. Fusion protein synthesized on such hybrid template is not present in the cell membrane but in the cytoplasm, where it permanently activates transduction pathway specific for RET. NTRK1 gene encoding a member of family of neuronal growth factor receptors containing thyrosine kinase domain is also rearranged in papillary cancers. However, genes fused to its kinase domain-encoding sequence are different from the ones fused to RET. MET, a gene encoding another membrane protein with thyrosine kinase activity, which acts as a growth factor-receptor, is overexpressed in 70%-90% of papillary thyroid cancers. BRAF gene encoding another yet kinase transducing signals from RAS and RAF to the cell is mutated at position 1796 (T/A, amino acid substitution V599E) in 38-69% of papillary cancers. The presence of this activatory mutation is associated with higher degree of clinical advancement of the disease. In addition, in majority of papillary cancers tested, mutations of the genes encoding nuclear triiodothyronine receptors were found. Transgenic mice with both TRB allele replaced with dominant-negative TRB mutants develop aggressive thyroid cancers. Progression from papillary to anaplastic cancer is most possibly caused by the occurrence of additional anomalies within P53, RAS, NM23,b-catenin gene and other genes.
Endokrynol Pol
PMID:[Genetic factors predisposing to the development of papillary thyroid cancer]. 1635 Jul 29

Lactoferrin (LF) is a protein secreted by the tissues of ectodermal origin. Its structure is similar to transferrin. LF appeared to be multifunctional, but its main functions are connected with the natural defense system of mammals. The biological role and origin of LF within brain in normal and disease processes are as yet uncharted. LF expression is greatly upregulated during neurodegenerative disorders and in elderly brains. LF may exert an antiinflammatory function via its inhibitory effect on hydroxyl radical formation. By antioxydative properties, LF prevents DNA damage and consequently tumor formation in the CNS. Moreover, LF specifically transactivates the p53 tumor suppressor gene. LF suppresses distress perception via opioid mediated mechanism and prevents a decrease of the immune system activity caused by psychosocial stress. Furthermore, LF possibly modulates behavior in man and in animals.
Neurol Neurochir Pol
PMID:[Lactoferrin in the central nervous system]. 1635 6

p63 is a developmentally regulated transcription factor related to p53, which activates and represses specific genes. The human AEC (Ankyloblepharon-Ectodermal dysplasia-Clefting) and EEC (Ectrodactyly-Ectodermal dysplasia-Cleft lip/palate) syndromes are caused by missense mutations of p63, within the DNA-binding domain (EEC) or in the C-terminal sterile alpha motif domain (AEC). We show here that p63 represses transcription of cell-cycle G(2)/M genes by binding to multiple CCAAT core promoters in immortalized and primary keratinocytes. The CCAAT-activator NF-Y and DeltaNp63alpha are associated in vivo and a conserved alpha-helix of the NF-YC histone fold is required. p63 AEC mutants, but not an EEC mutant, are incapable to bind NF-Y. DeltaNp63alpha, but not the AEC mutants repress CCAAT-dependent transcription of G(2)/M genes. Chromatin immunoprecipitation recruitment assays establish that the AEC mutants are not recruited to G(2)/M promoters, while normally present on 14-3-3sigma, which contains a sequence-specific binding site. Surprisingly, the EEC C306R mutant activates transcription. Upon keratinocytes differentiation, NF-Y and p63 remain bound to G(2)/M promoters, while HDACs are recruited, histones deacetylated, Pol II displaced and transcription repressed. Our data indicate that NF-Y is a molecular target of p63 and that inhibition of growth activating genes upon differentiation is compromised by AEC missense mutations.
 ...
PMID:Mechanisms of transcriptional repression of cell-cycle G2/M promoters by p63. 1647 49

The objective of this study was to evaluate the expression of bcl-2 in Dukes' stage B and stage C (AJCC/UICC stage I and III) colorectal adenocarcinomas and to examine its association with clinicopathological features, p53, ki-67 and long term outcome. Paraffin embedded specimens from 61 patients with Dukes' stage B (AJCC/UICC stage I) and 39 patients with Dukes' stage C (AJCC/UICC stage III) colorectal adenocarcinoma who were treated with surgery were assessed. We used immunohistochemistry to determine the expression of bcl-2, p53 and ki-67 with a five-year follow-up. Positive bcl-2 expression was seen in 27 cases (27%). Expression of bcl-2 protein was related to tumor stage (p=0.0117). There was very strong evidence of an association between bcl-2 staining and ki-67 score (p<0.001). There was a trend towards increased survival in patients whose tumors expressed bcl-2 protein (p=0.001). When entered into a multivariate analysis model, which also included p53 and stage, bcl-2 staining emerged as a prognostic indicator variable. Expression of bcl-2 appears to be useful in selecting a group of colorectal cancer patients with a better prognosis.
Pol J Pathol 2005
PMID:Immunohistochemical expression of bcl-2 in Dukes' stage B and C colorectal carcinoma patients: correlation with p53 and ki-67 in evaluating prognostic significance. 1647 77

Oxidative stress and certain environmental carcinogens, e.g. vinyl chloride and its metabolite chloroacetaldehyde (CAA), introduce promutagenic exocyclic adducts into DNA, among them 1,N(6)-ethenoadenine (epsilonA), 3,N(4)-ethenocytosine (epsilonC) and N(2),3-ethenoguanine (epsilonG). We studied sequence-specific interaction of the vinyl-chloride metabolite CAA with human p53 gene exons 5-8, using DNA Polymerase Fingerprint Analysis (DPFA), and identified sites of the highest sensitivity. CAA-induced DNA damage was more extensive in p53 regions which revealed secondary structure perturbations, and were localized in regions of mutation hot-spots. These perturbations inhibited DNA synthesis on undamaged template. We also studied the repair kinetics of CAA-induced DNA lesions in E. coli at nucleotide resolution level. A plasmid bearing full length cDNA of human p53 gene was modified in vitro with 360 mM CAA and transformed into E. coli DH5alpha strain, in which the adaptive response system had been induced by MMS treatment before the cells were made competent. Following transformation, plasmids were re-isolated from transformed cultures 35, 40, 50 min and 1-24 h after transformation, and further subjected to LM-PCR, using ANPG, MUG and Fpg glycosylases to identify the sites of DNA damage. In adaptive response-induced E. coli cells the majority of DNA lesions recognized by ANPG glycosylase were removed from plasmid DNA within 35 min, while MUG glycosylase excised base modifications only within 50 min, both in a sequence-dependent manner. In non-adapted cells resolution of plasmid topological forms was perturbed, suggesting inhibition of one or more bacterial topoisomerases by unrepaired epsilon-adducts. We also observed delayed consequences of DNA modification with CAA, manifesting as secondary DNA breaks, which appeared 3 h after transformation of damaged DNA into E. coli, and were repaired after 24 h.
Acta Biochim Pol 2006
PMID:Sequence-specific p53 gene damage by chloroacetaldehyde and its repair kinetics in Escherichia coli. 1658 87

Normal somatic cells divide in vitro only for a limited number of times, and then enter a state of replicative senescence. In most human cells replicative senescence is triggered by critical shortening and uncapping of telomeres, which leads to the up-regulation of p53 and/or p16 suppressor proteins that inhibit cell divisions. Because both reconstruction of telomeres and inactivation of suppressor proteins enables the cells to grow further or even immortalize, it has been hypothesized that replicative senescence acts as a natural barrier against neoplastic transformation. On the other hand, however, recent reports suggest that the accumulation of senescent cells may jeopardize tissue integrity and create a specific microenvironment that promotes tumorogenesis in elderly people. In this review we describe recent advances in our knowledge on the mechanisms of replicative senescence and discuss its medical implications.
Pol Arch Med Wewn 2005 Sep
PMID:[Mechanisms and medical implications of replicative senescence]. 1670 69

The aim of this study was to analyze the molecular mechanism of inositol hexaphosphate (InsP(6)) action through which it may inhibit proliferation of colon cancer cells and cell cycle progression. A kinetic study of p53 and p21(WAF1) mRNA increase was performed on human colon cancer HT-29 cells after treatment with 1, 5 and 10 mM InsP(6) for 6, 12, 24 and 48 h. Real-time-QPCR based on TaqMan methodology was applied to analyze quantitatively the transcript levels of these genes. The transcription of beta-actin and GAPDH genes was assessed in parallel to select the control gene with least variability. The 2(-Delta Delta Ct) method was used to analyze the relative changes in gene transcription. InsP(6) stimulated p53 and p21(WAF1) expression at the mRNA level, with the highest increase in p21(WAF1) mRNA occurring at 24 h, i.e., following the highest increase in p53 mRNA observed at 12 h. Based on these studies it may be concluded that the ability of InsP(6) to arrest the cell cycle may be mediated by the transcriptional up-regulation of the p53-responsive p21(WAF1) gene.
Acta Biochim Pol 2006
PMID:Quantitative analysis of the level of p53 and p21(WAF1) mRNA in human colon cancer HT-29 cells treated with inositol hexaphosphate. 1673 61

The purpose of the study was a pathomorphological and immunohistochemical analysis of tumour cells and connective tissue in equine sarcoids. Investigations were performed using histopathological, ultrastructural, immunohistochemical (PCNA, p53, cytokeratin, vimentin) and histochemical (Ag-NORs) methods. The study was conducted on 50 sarcoids originating from 36 horses and classified as occult, verrucous, fibroblastic and a mixed type of sarcoid based on their clinical appearance. Most of the tumours were located on the girth (30%), neck (24%), head (12%), and legs (12%). The average age of the horses at the first clinical examination was 5.7 years. The sarcoids occurred on the skin of mares (61%), geldings (31%) and stallions (8%), the predominant was Wielkopolska breed (41%) and mixed breeds with Wielkopolska breed (41%). The predominant colour was bay (80%). The data showed that the presence of characteristic, microscopic features was variable but it was not consistent enough to allow differentiation of the clinical types based on histopathology. PCNA expression was not characteristic for the clinical type of sarcoid but it appeared to be a useful tool for the determination of the biological activity of the tumour and the probability of its recurrence. No relationship was found between AgNORs and cell proliferation. The study demonstrated the presence of p53 positive cells in the epidermal and fibroblastic portions. Numerous p53-positive cells were observed in the sarcoids and tended to recurrence. The staining for cytokeratin and vimentin makes the diagnosis of tumour easier. The immunohistochemical studies of PCNA, and p53 are of great significance to the prognosis.
Pol J Vet Sci 2006
PMID:Pathomorphological and immunohistochemical study of selected markers of tumour cell proliferation in equine sarcoids. 1678 Jan 78

We developed a real-time PCR assay for measuring relative quantities (RQ) of p53 tumor suppressor mRNA in the whitefish (Coregonus lavaretus, Salmonidae, Teleostei). Real-time PCR primers for the p53 gene were designed from a region that was found to be conserved among salmonid p53 genes. To test for the usefulness of the assay we performed a treatment study, using benzo[a]pyrene (B[a]P) a putative p53-inducer. Two groups of hatchery raised whitefish, with an average body mass of 15 g and total length of 12 cm were either given an intraperitoneal injection (10 mg x kg(-1)) of B[a]P in corn oil (2 mg B[a]P ml(-1) corn oil) or corn oil alone (Control). After treatment (48 h, 7 degrees C), two random fish from each group were anesthetized and the liver, head kidney and brain were collected for mRNA isolation and analysis. In the control fish, relative quantification analysis based on the p53 mRNA levels in liver (RQ=1.00) showed higher basal levels of p53 mRNA in the head kidney (RQ= 1.69), and lower in the brain (RQ=0.41). In all three tissues sampled, p53 mRNA was affected by treatment with B[a]P. Liver tissue showed the greatest induction (RQ=1.53) from base levels (RQ=1.00), followed by brain (RQ=1.36), and head kidney (RQ=1.23). These results confirm that p53 mRNA is generally present at lower levels in differentiated tissues (liver and brain) than in those tissues with cell lines (head kidney), and demonstrate that p53 is moderately inducible by B[a]P in the whitefish. The approach presented here has the advantage of providing rapid and accurate measures of p53 induction in various tissues of fish responding to PAH contaminant exposure.
Pol J Vet Sci 2006
PMID:Real-time PCR analysis of p53 mRNA levels in tissues of whitefish (Coregonus lavaretus) exposed to benzo[a]pyrene. 1678 Jan 82


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