Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

A new animal model for the causation of liver tumors via a bacterial infection presented itself fortuitously in the form of a new species, Helicobacter hepaticus. This species of Helicobacter colonizes the hepatic bile canaliculi in susceptible strains of mice, resulting in hepatitis and hepatocellular and hepatocholangiolar adenomas and carcinomas. The mechanism by which this infection leads to cancer is unknown. Tests with Helicobacter hepaticus have revealed thus far that the bacteria do not secrete a mutagen which is capable of detection by the Ames Assay. Measurement of oxidatively damaged bases in the liver DNA of hepaticus infected mice have shown accumulation of 8-oxodeoxyguanosine with disease progression. Other promutagenic DNA lesions, 7-methylguanine and O6-methylguanine, indicative of nitrosation of endogenous amines by nitric oxide, were not detected. Analysis of carcinomas and adenomas taken from H. hepaticus infected A/JCr mice revealed no mutations in ras oncogenes or in exons 5-8 of the p53 gene. These preliminary results indicate that a non-genotoxic tumor promotion mechanism, possibly implemented by reactive oxygen species from the immune response, is more likely than a genotoxic mechanism.
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PMID:Liver tumorigenesis by Helicobacter hepaticus: considerations of mechanism. 879 29

A strong association was found to exist between patterns of lymphoid malignancies and socioeconomic status. B-cell lymphomas and T-acute lymphoblastic leukemia are much more prevalent in developing countries where the chances of acquiring infections especially at a younger age are high. B-cell precursor acute lymphatic leukemia, however, are much more prevalent in the Western world. Many infectious agents are associated with lymphatic malignancies. Epstein-Barr virus is involved in African Burkitt's lymphoma, human immunodeficiency virus-related Burkitt's lymphoma, lymphoproliferative syndrome post-transplantation, and Hodgkin's disease. Other infectious agents which may play a role in lymphoproliferative disorders are human immunodeficiency virus in acquired immune deficiency syndrome-associated lymphoma, human T-lymphotropic virus in adult T-cell lymphoma, Helicobacter pylori in mucosa-associated lymphoid tissue lymphoma, theileriosis in lymphoproliferative syndrome in cattle, Avian leukosis virus in chicken bursal lymphoma, and possibly a bacterial infection in immunoproliferative small intestine disease, potentially reversed by antibiotic therapy. The association between infectious agents and hematologic malignancies may be explained by the creation of large populations of activated cells followed by higher occurrences of 'genetic accidents'. This theory may be reinforced in at least some malignancies with the existence of viral proteins which either have complex relationships with key cellular gene products like p53 and Rb which have roles in cell cycle control, or share common motifs with bc1-2, therefore operating as anti-apoptotic elements. Whenever these genes are deranged, cell deoxysibonucleic acid repair or apoptosis are no longer possible, thereby creating a state of genome instability, increased acquisition of mistakes, and increased chances for malignant transformation.
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PMID:Infectious agents and environmental factors in lymphoid malignancies. 881 40

Helicobacter hepaticus is a recently discovered bacterium that invades mouse liver causing chronic active hepatitis followed by development of preneoplastic hepatocellular foci, hepatocellular adenomas and carcinomas. This establishes a unique animal model for study of the mechanisms of cancer development due to a chronic bacterial infection. A possible mechanism of bacteria-associated tumorigenesis is mutation of oncogenes or tumor suppressor genes. Since mutations in ras oncogenes have been widely detected in a variety of chemically induced and spontaneous mouse liver tumors and specific mutations in the p53 tumor suppressor gene have been associated with human bladder cancers attributed to chronic schistosomal infection, we studied exons 1 and 2 of the N-, K- and H-ras genes and exons 5-8 of the p53 gene for the presence of point mutations in 25 liver tumors from 10 naturally infected A/JCr mice, ranging in age from 16 to 24 months. The 20 adenomas and five carcinomas varied in size from 0.1 to 2.3 cm and arose in livers characterized by a wide assortment of pathological profiles, including hepatitis, inflammation, hyperplasia, hypertrophy, leukocyte infiltration, necrosis and focal phenotypic alteration. DNA samples extracted from formalin-fixed paraffin-embedded tissues were screened by PCR/SSCP analysis and showed no mutations in the analyzed genes. Complete absence of mutations in ras genes in 25 mouse liver tumors is unusual. Other genes may be targeted or H. hepaticus infection causes liver cancer through other pathways than direct damage to DNA.
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PMID:Lack of p53 and ras mutations in Helicobacter hepaticus-induced liver tumors in A/JCr mice. 905 12

Apoptosis is a key phenomenon in the regulation of the life span of terminally differentiated leukocytes. Human gingiva represents an established model to study immune responses to bacterial infection. In this investigation, we used the TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) technique to evaluate presence and topographic location of apoptosis-associated DNA damage in human gingival biopsies along with the expression of the p53 and Bcl-2 apoptosis-regulating proteins. Qualitative data analysis showed high densities of cells expressing DNA damage and p53 both within the epithelial attachment to the tooth and in the perivascular infiltrate (infiltrated connective tissue [ICT]) immediately underlying the site of chronic bacterial aggression. Topographic consistency between DNA damage- and p53-positive cells was consistently observed. Quantitative analysis of the ICT showed mean densities of DNA damage- and p53-positive cells of 345 +/- 278 and 403 +/- 182 cells/mm2, respectively. Numerical consistency was confirmed by multivariate regression analysis: densities of DNA damage-positive cells were significantly predicted by densities of p53-positive cells (P = 0. 001, r2 = 0.84). In the ICT, cells displaying biotinylated DNA nicks were 3.8% +/- 2.7% of total cellularity, while p53- and Bcl-2-positive cells represented 4.4% +/- 1.7% and 15.4% +/- 6.7% of total cells, respectively. It is suggested that p53 expression associated with DNA damage is a prevalent phenomenon in chronically inflamed human gingiva, and that apoptosis may be a relevant process for the maintenance of local immune homeostasis at sites of chronic bacterial challenge in vivo.
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PMID:In situ detection of apoptosis at sites of chronic bacterially induced inflammation in human gingiva. 978 21

The development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is dependent on Helicobacter pylori infection. Bacterial colonisation of the gastric mucosa triggers lymphoid infiltration and the formation of acquired MALT. The bacterial infection induces and sustains an actively proliferating B-cell population through direct (autoantigen) and indirect (intratumoral T cells specific for H. pylori) immunological stimulation. Moreover, the bacterial infection provokes a neutrophilic response, which causes the release of oxygen free radicals. These reactive species may promote the acquisition of genetic abnormalities and malignant transformation of reactive B cells. A transformed clone carrying the translocation t(1;18)(q21;q21) forms a MALT lymphoma, the growth of which is independent of H. pylori and will not respond to bacterial eradication. Malignant clones without t(11;18)(q21;q21), but with other genetic abnormalities, such as trisomy 3 or microsatellite instability, depend critically on immune stimulation mediated by H. pylori for their clonal expansion. In the early stages, the tumour can be successfully treated by eradication of the bacterium, whereas at later stages the tumour may escape its growth dependency through acquisition of additional genetic abnormalities such as t(1;14)(p22;q32) and t(1;2)(p22,p12) involving the BCL-10 gene. Finally, further genetic abnormalities, such as inactivation of the tumour suppressor genes, p53 and p16, can lead to high-grade transformation. Detection of these abnormalities may help with the clinical management of patients with gastric MALT lymphoma.
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PMID:Gastric MALT lymphoma: from aetiology to treatment. 1190 29

Human newborns are more susceptible than adults to bacterial infection. With gram-negative bacteria, this may be due to a diminished response of newborn leukocytes to lipopolysaccharide (LPS). Since protein tyrosine kinase inhibition abolishes LPS priming in adult cells, we hypothesized that protein tyrosine kinases may have a critical role in LPS priming of polymorphonuclear neutrophils (PMNs) and that newborn PMNs may have altered protein tyrosine kinase activities. In the present study, we investigated the role of src family protein tyrosine kinases in the LPS response of newborn PMNs compared to adult cells. In a respiratory assay, the LPS-primed increase in formylmethionylleucylphenylalanine (fMLP)-triggered O2- release by adult PMNs was greatly decreased by PP1 [4-amino-5-(4-methyphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine], a src kinase inhibitor, to the level of untreated newborn PMNs, in which LPS failed to prime. LPS activated the src-like kinases p59hck (HCK) and p58fgr (FGR) in both adult and newborn PMNs but increased the activation of p53/56lyn (LYN) only in adult cells. In newborn PMNs, LYN was highly phosphorylated independent of LPS. We evaluated subcellular fractions of PMNs and found that the phosphorylated form of LYN was mainly in the Triton-extractable, cytosolic fraction in adult PMNs, while in newborn cells it was located mainly in Triton-insoluble, granule- and membrane-associated fractions. In contrast, the phosphorylated mitogen-activated protein kinases ERK1/2 and p38 were mainly detected in the cytosol in both adult and newborn PMNs. These data indicate a role for LYN in the regulation of LPS priming. The trapping of phosphorylated LYN in the membrane-granule fraction in newborn PMNs may contribute to the deficiency of newborn cells in responding to LPS stimulation.
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PMID:Role of protein tyrosine kinase p53/56lyn in diminished lipopolysaccharide priming of formylmethionylleucyl- phenylalanine-induced superoxide production in human newborn neutrophils. 1550 76

A boy with lifelong recurrent bacterial infection at cutaneous and mucosal sites was investigated. PMN oxidative burst to phorbol myristate acetate (PMA) and zymosan was normal but was increased 20- to 50-fold upon C5a or formyl-met-leu-phe (fMLP) chemoattractant stimulation, accompanied by accelerated PMN apoptosis. His PMNs showed increased constitutive tyrosine phosphorylation of 21-, 25-, and 44-kDa proteins, and of src-family kinases (p59(hck), p58(fgr), and p53/56(lyn)). Phosphorylation was abnormally enhanced following fMLP stimulation. Expression and activity of the major PMN tyrosine phosphatases, i.e., CD45, CD148, and SHP-1 and -2, was normal. However, dephosphorylation of phospho-p58(fgr) and phospho-p53/56(lyn) by lysates of patient's PMNs was enhanced. Thus, another phosphatase may be overactive, perhaps dephosphorylating a regulatory (inhibitory) site on a protein tyrosine kinase, accounting for the abnormal PMN tyrosine phosphorylation and function. With age (now 13 years), T-cell lymphopenia and loss of T-cell responses developed. This appears to be a unique primary immunodeficiency with abnormal PMN oxidative and apoptotic responses to chemoattractants, dysregulated protein tyrosine phosphorylation, serious bacterial infection, and T-lymphocyte attrition.
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PMID:Increased chemoattractant induced neutrophil oxidative burst, accelerated apoptosis, and dysregulated tyrosine phosphorylation associated with lifelong bacterial infections. 1601 63

Although mainly expressed in neuronal cells, lipocalin-type PGD synthase (L-PGDS) is detected in the macrophages infiltrated to atherosclerotic plaques. However, the regulation and significance of L-PGDS expression in macrophages are unknown. Here, we found that treatment of macrophages with bacterial endotoxin (LPS) or Pseudomonas induced L-PGDS expression. Epigenetic suppression of L-PGDS expression in macrophages blunted a majority of PGD(2) produced after LPS treatment. Chromatin immunoprecipitation assays show that L-PGDS induction was regulated positively by AP-1, but negatively by p53. L-PGDS expression was detected in whole lung and alveolar macrophages treated with LPS or Pseudomonas. L-PGDS overexpressing transgenic mice improved clearance of Pseudomonas from the lung compared with nontransgenic mice. Similarly, intratracheal instillation of PGD(2) enhanced removal of Pseudomonas from the lung in mice. In contrast, L-PGDS knockout mice were impaired in their ability to remove Pseudomonas from the lung. Together, our results identify induction of L-PGDS expression by inflammatory stimuli or bacterial infection, the regulatory mechanism of L-PGDS induction, and the protective role of L-PGDS expression in host immune response. Our study suggests a potential therapeutic usage of L-PGDS or PGD(2) against Pseudomonas pneumonia.
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PMID:Induction and function of lipocalin prostaglandin D synthase in host immunity. 1767 19

Bacterial infection has been associated with several malignancies, yet the exact mechanism of infection-associated carcinogenesis remains obscure. Furthermore, it is still not clear whether oncontransformation requires an active infection process, or merely the presence of inactivated bacteria remnants is enough to cause deleterious effects. Here, we analyzed whether or not consumption of non-pathogenic and pathogenic heat-killed Escherichia coli leads to changes in genome stability in somatic tissues of exposed animals. For one week, mice were given to drink filtered or not-filtered water contaminated with heat-killed non-pathogenic E. coli DH5alpha or heat-killed pathogenic E. coli O157:H7 Sakai. Control animals received tap water. One week after exposure, molecular changes were analyzed in the small intestine, an organ that is in immediate contact with contaminated water. Additionally, we studied the effect in the distant spleen and liver, the organs that are involved in an immune response and detoxification, respectively. Finally, muscles were chosen as neutral tissues that were not supposed to be affected. Intestinal, liver and spleen but not muscle cells responded to all bacterial treatments with an increased level of DNA damage monitored by the induction of gammaH2AX foci. In the intestine, elevated levels of DNA damage were in parallel with an increase in Ku70 and p53 expression. We have also found an elevated level of cellular proliferation in the intestine, liver and spleen but not in muscle tissues of all exposed animals as measured by increase in PCNA levels. Our data suggest that exposure to heat-killed filtered bacteria can trigger substantial molecular responses and cause genomic instability in target and distant organs. Even though bacteria were non-pathogenic and unable to cause infection, their remnants still caused a profound effect on exposed animals.
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PMID:Heat-killed bacteria induce genome instability in mouse small intestine, liver and spleen tissues. 1955 Jan 53

Inflammation and hepatic stellate cell (HSC) activation are the most crucial steps in the formation of hepatic fibrosis. Hepatocytes damaged by viral or bacterial infection, alcohol or toxic chemicals initiate an inflammatory response that activates collagen production by HSCs. Recent studies indicate curcumin has liver-protective effects due to its anti-inflammatory, antioxidant and anticancer activities; however, the mechanisms are not well understood. In this study, we show that curcumin protected against hepatic fibrosis in BALB/c mice in vivo by inhibiting HSC activation, inflammatory responses and inducing apoptosis of damaged hepatocytes. Using the thioacetamide (TAA)-induced hepatic fibrosis animal model, we found that curcumin treatment up-regulated P53 protein expression and Bax messenger RNA (mRNA) expression and down-regulated Bcl-2 mRNA expression. Together, these responses increased hepatocyte sensitivity to TAA-induced cytotoxicity and forced the damaged cells to undergo apoptosis. Enhancing the tendency of damaged hepatocytes to undergo apoptosis may be the protective mechanism whereby curcumin suppresses inflammatory responses and hepatic fibrogenesis. These results provide a novel insight into the cause of hepatic fibrosis and the cytoprotective effects curcumin has on hepatic fibrosis suppression.
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PMID:Curcumin protects against thioacetamide-induced hepatic fibrosis by attenuating the inflammatory response and inducing apoptosis of damaged hepatocytes. 2222 74


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