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)

Apoptosis is a form of genetically programmed cell death, which plays a key role in regulation of cellularity in a variety of tissue and cell types including the cardiovascular tissues. Under both physiological and pathophysiological conditions, various biophysiological and biochemical factors, including mechanical forces, reactive oxygen and nitrogen species, cytokines, growth factors, oxidized lipoproteins, etc., may influence apoptosis of vascular cells. The Fas/Fas ligand/caspase death-signaling pathway, Bcl-2 protein family/mitochondria, the tumor suppressive gene p53, and the proto-oncogene c-myc may be activated in atherosclerotic lesions, and mediates vascular apoptosis during the development of atherosclerosis. Abnormal expression and dysfunction of these apoptosis-regulating genes may attenuate or accelerate vascular cell apoptosis and affect the integrity and stability of atherosclerotic plaques. Clarification of the molecular mechanism that regulates apoptosis may help design a new strategy for treatment of atherosclerosis and its major complication, the acute vascular syndromes.
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PMID:Molecular signal transduction in vascular cell apoptosis. 1178 70

Protein sulfhydryl groups can undergo reversible oxidation reactions in response to reactive oxygen and reactive nitrogen species. Sensitive detection of sulfhydryl group oxidation in specific proteins is required to further our understanding of protein redox changes in biological systems. In general, to detect reversible oxidation reactions the oxidized sulfur atom is reduced to a sulfhydryl group followed by a reaction with a quantifiable agent. Our aim was to develop a sensitive method to detect reversibly oxidized protein sulfhydryl groups in a Western blot format. Conjugation of methoxypolyethylene glycol-maleimide (MAL-PEG) to protein sulfhydryl groups was optimized. Once MAL-PEG forms a covalent bond with the protein, the MAL-PEG-protein conjugate can be detected as a band shift by western analysis. The efficiency of MAL-PEG conjugation to protein was determined with creatine kinase. MAL-PEG conjugated to approximately 100% of the available sulfhydryl groups on creatine kinase within 30 min. Band shift detection sensitivity was measured using the redox-regulated protein p53. MAL-PEG conjugation coupled to western analysis detected a minimum of 0.23 pmol of oxidized p53. The MAL-PEG conjugation method described in this communication can be used to assess the reversible sulfhydryl oxidation status of proteins for which antibodies suitable for western analysis are available.
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PMID:Development of a sensitive assay to detect reversibly oxidized protein cysteine sulfhydryl groups. 1181 84

In some neurological disorders, excessive nitric oxide (NO, nitrogen monoxide) produced by inducible and/or neuronal nitric oxide synthases (iNOS and nNOS) is able to combine with superoxide (O(minus sign)(2)) to form peroxynitrite (ONOO(minus sign)), which can then induce p53-dependent neural apoptosis. In the present study, experiments using p53 knock-out mice primary neural cells revealed that 3-morpholinosydnonimine hydrochloride (SIN-1), a peroxynitrite donor, triggered apoptosis, while p53-transcriptional activity was effectively suppressed in the absence of p53 molecules. This shows that SIN-1 was able to induce p53-dependent apoptosis in murine primary neural cells. The mechanism responsible for the SIN-1-induced accumulation of p53 molecules was then analyzed. Western blot analysis indicated that p53 accumulation caused by SIN-1 did not require p53 phosphorylation, whereas SIN-1 treatment triggered MAP kinase (MAPK) phosphorylation and pretreatment with the MAP kinase kinase (MEK) inhibitor U0126 inhibited p53 accumulation. Pretreatment of the neural cells with lovastatin, an inhibitor of p21(ras) signaling, greatly inhibited the accumulation of p53 induced by SIN-1. Northern blot and immunofluorescence analyses revealed that primary neural cells treated with SIN-1 had increased levels of p19 alternate reading frame (p19(ARF)) mRNA and protein, which is induced by MAPK and stabilizes the p53 protein. Our findings clearly show that the p21(ras)-MAPK-p19(ARF) pathway has an essential role in p53-dependent apoptosis triggered by peroxynitrite in neural cells.
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PMID:3-Morpholinosydnonimine hydrochloride induces p53-dependent apoptosis in murine primary neural cells: a critical role for p21(ras)-MAPK-p19(ARF) pathway. 1189 Jul 36

P53 is known as a determinant of cellular responses to DNA damage, including apoptosis, cell cycle arrest, and DNA repair. Its role is most easily understood in the context of Burkitt lymphoma and other apoptosis-prone cell types. A number of epithelial cancer cell types, by contrast, exhibit a higher threshold for apoptosis induction in response to DNA damage. In fact, p53 mediates DNA repair and protective responses in the latter cell types, in some cases p53-deficient cells being more sensitive to DNA damage, antithetical to the situation in Burkitt lymphoma and other apoptosis-prone cell types. Ultraviolet light, cisplatin, and nitrogen mustards produce damage that is repaired by a p53-regulated pathway. Here, we explore the sensitivity of the platinum compound oxaliplatin and thio-TEPA (N, N', N", triethylenethiophosphoramide), a cancer chemotherapeutic agent that produces largely base damage, in p53-defective cells. This work demonstrates that the contribution of p53 temporally correlates with DNA repair pathways to produce a resistant phenotype, while the p53-defective cells are more sensitive to certain DNA-damaging chemotherapeutic agents.
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PMID:Sensitivity of p53-deficient cells to oxaliplatin and thio-TEPA (N, N', N" triethylenethiophosphoramide). 1205 67

p53 suppressor gene mutations are a well known step which occurs in the late stages of the complex tumourigenesis of colorectal cancer. A deregulation of p53 protein function may be associated with increased neovascularization and aggressive tumour growth. In vitro studies have shown that these genetic alterations cause a loss of wild-type p53-induced anti-angiogenetic control and could possibly induce expression of the neoangiogenic vascular endothelial growth factor (VEGF). Therefore, this in vivo study was performed to assess p53 mutations, i.e. hot spots in exons 4-9, in primary colorectal cancers and in corresponding liver metastases in order to test whether there is an association between p53 mutated tumours with increased microvessel density (MVD) and VEGF overexpression. Twenty-two tissue samples taken from primary colorectal cancers and the corresponding liver metastases were immediately snap-frozen in liquid nitrogen and fixed in formaldehyde. After DNA extraction exons 4-9 were amplified and directly sequenced. Cryostat sections were stained immunohistochemically using antibodies against VEGF, CD34, and p53 protein. A modified semiquantitative Weidner score and interactive computerized image analysis was used to assess MVD. Overexpression of immunohistochemically detected p53 protein was found in 7 of the 11 primary tumours and liver metastases (64%). Sequencing showed 3 out of 11 primary tumours (27%) and 5 out of 11 liver metastases (46%) to have p53 point or frameshift mutations; these samples tested immunohistochemically positive for p53 protein. Two p53 mutations in samples of liver metastases were not detectable in the corresponding primaries. We detected one frameshift mutation in exon 4 that has not yet been described in the literature. Tumour samples with p53 mutations and increased VEGF immunoreactivity were associated with higher MVD (p<0.01 and p<0.05, respectively). However, there was no association detected immunohistochemically between p53 and MVD as well as p53 mutations and VEGF overexpression. Our data demonstrate specific genetic alterations in the coding regions of p53 suppressor gene in both primary colorectal cancers and corresponding liver metastases, these alterations are associated with an increase in MVD, but not in VEGF overexpression. In addition, a novel frameshift mutation in both colorectal cancer and metastasis is described.
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PMID:Association of p53 mutations, microvessel density and neoangiogenesis in pairs of colorectal cancers and corresponding liver metastases. 1211 17

Asbestos fibers produce diffuse malignant mesotheliomas in chronic rodent inhalation assays or after direct intrapleural or intraperitoneal injection. In vitro models have provided evidence that asbestos fibers are genotoxic carcinogens that can directly or indirectly generate reactive oxygen- and nitrogen-derived species that cause DNA damage. Heterozygous p53+/- mice show an increased incidence and reduced latency of malignant mesotheliomas induced by weekly intraperitoneal injections of crocidolite asbestos fibers. In this study, we investigated whether loss of heterozygosity (LOH) at the p53 tumor-suppressor gene locus contributes to accelerated tumor progression. LOH was found in 50% of the tumors produced in heterozygous p53+/- mice. In contrast to tumors that arise in p53+/+ mice or those that retained one p53 allele, LOH was associated with large tumor masses with central areas of necrosis, local invasion, and penetration of lymphatics. Increased tumor size was not associated with increased levels of cell proliferation as determined by BrdU incorporation, but it was correlated with a reduction in apoptosis as determined morphologically and by the TUNEL assay. Wild-type p53 protein is essential for cell cycle arrest in response to DNA damage and in maintenance of genomic stability. Cell lines established from tumors that showed LOH at the p53 tumor-suppressor gene locus were nearly tetraploid. These results suggest that p53 haplo-insufficiency sensitizes mice to the clastogenic or aneuploidogenic effects of crocidolite asbestos fibers, resulting in a shorter latent period. As solid tumors develop, spontaneous loss of the wild-type allele accompanied by decreased apoptosis and genetic instability is associated with accelerated tumor growth, invasion, and lymphatic dissemination.
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PMID:Accelerated progression of asbestos-induced mesotheliomas in heterozygous p53+/- mice. 1215 29

Pamidronate belongs to the class of nitrogen-containing bisphosphonates that are potent inhibitors of bone resorption frequently used for the treatment of osteoporosis and cancer-induced osteolysis. The inhibition of osteoclasts' growth has been suggested as the main mechanism of the inhibitory effect of pamidronate on bone metastases. Recent findings indicated that bisphosphonates also have a direct apoptotic effect on other types of tumour cells. Nitrogen-containing bisphosphonates were shown to inhibit farnesyl diphosphate synthase, thus blocking the synthesis of higher isoprenoids. By this mechanism they inactivate monomeric G-proteins of the Ras and Rho families for which prenylation is a functional requirement. On the background of the known key role of G-proteins in tumorigenesis, we investigated a possible beneficial use of pamidronate in the treatment of malignant melanoma. Our results indicate that pamidronate inhibits the cell growth and induces apoptosis in human melanoma cells in vitro. Susceptibility to pamidronate did not correlate to CD95 ligand sensitivity or p53 mutational status. Furthermore it is interesting to note that overexpression of bcl-2 did not abolish pamidronate-induced apoptosis. These data suggests that pamidronate has a direct anti-tumour effect on malignant melanoma cells, independently of the Bax/Bcl-2 level.
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PMID:The bisphosphonate pamidronate induces apoptosis in human melanoma cells in vitro. 1217 10

Apoptosis and long term enterocyte survival were examined in vivo after exposure to three cytotoxic agents (Cisplatin, Nitrogen Mustard and N-methyl-N-nitrosourea (NMNU/MNU)) within mice either singly or doubly mutant for p53 and Msh2. P53 deficiency caused abrogation of the immediate apoptotic response to each agent, but only led to increased survival after cisplatin treatment. Msh2 deficiency reduced the apoptotic response to each agent, but only led to increased crypt survival after NMNU treatment. Following cisplatin treatment, the response of (Msh2(-/-), p53(-/-)) mice paralleled that of the p53(-/-) mice. A delayed wave of apoptosis was observed in both p53(-/-) and (Msh2(-/-), p53(-/-)) mice demonstrating this phenomenon to be independent of functional Mismatch repair (MMR). We conclude that loss of either p53 or Msh2 dependent apoptosis does not predict long-term crypt survival in vivo, however genetic status clearly can modulate survival for some agents such as cisplatin.
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PMID:The ability to engage enterocyte apoptosis does not predict long-term crypt survival in p53 and Msh2 deficient mice. 1218 94

The high frequency of G-->T transversions in the p53 gene is a distinctive feature of lung cancer patients with a smoking history and is commonly believed to reflect the direct mutagenic signature of polycyclic aromatic hydrocarbon (PAH) adducts along the gene. Using the April 2000 update of the p53 mutation database of the International Agency for Research on Cancer together with the primary literature, we confirm that the frequency of p53 G-->T transversions in lung cancer of smokers is about three times higher than their frequency in lung cancer of nonsmokers and in most other smoke-unrelated cancers. In contrast, the frequency of C-->A transversions, the DNA-strand mirror counterpart of G-->T transversions, appears to be similar in virtually all human cancers. Along with other data, this strand bias leads us to suggest that smoking may inhibit repair of G-->T primary lesions on the non-transcribed strand. As to the origin of G-->T primary lesions in the p53 gene, we unexpectedly found that cell lines derived from lung cancers, but not from other cancers, demonstrate significant additional excess of G-->T transversions when compared to p53 mutations in parent primary tumors. A detailed codon-by-codon comparison provides evidence in favor of the in vitro origin of this culture-associated G-->T augmentation. Since in culture lung cancer cell lines are not exposed to the carcinogens from smoke, one would rather ascribe these new G-->T transversions to some other mutagens such as, for example, reactive oxygen and nitrogen species. These results are consistent with our previous report [Proc. Natl. Acad. Sci. U.S.A. 97 (2000) 12244], and suggest that other factors, in addition to the direct mutagenic action of PAH-like carcinogens, contribute to p53 mutation-associated lung malignancy.
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PMID:On the origin of p53 G:C --> T:A transversions in lung cancers. 1237 56

Rheumatoid arthritis (RA) and osteoarthritis (OA) are polygenic diseases. Polymorphisms in candidate genes have been studied for possible association with susceptibility to disease development. Aside from HLA polymorphisms, of particular interest are those in genes encoding cytokines, signaling molecules, and enzymes involved in the production and catabolism of oxygen and nitrogen radicals. Cytokines are involved in the modulation of the pathological process and have been the target for novel therapeutic interventions. Evidence for their involvement in RA and OA has been provided from genetic analyses in patient populations as well as from animal models of disease. Intracellular signaling cascades control cellular responses and thus regulate many aspects of the pathology manifested in rheumatic diseases. Deciphering the organization and activity of such signaling pathways in disease is underway. Polymorphisms have been identified in gene promoter regions regulating efficient binding of transcription factors, and in coding regions of genes whose products are involved in signal cascades relevant to RA. Among these are the NF-kappaB pathway, steroid receptors and the p53 tumor suppressor gene. Both reactive oxygen species (ROS) and reactive nitrogen species (RNS) have also been implicated in rheumatic diseases. It is thought that excess, damaging, ROS/RNS may arise from an imbalance between the production and removal of these chemical species. Polymorphisms in genes that encode enzymes involved in either generating or degrading ROS/RNS may contribute to such an imbalance. In the last few years, polymorphisms in such genes have indeed been identified as risk factors for rheumatic diseases.
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PMID:Advances in understanding the genetic basis of rheumatoid arthritis and osteoarthritis: implications for therapy. 1242 Oct 93


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