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)

DNA damage results in an increase in P53 levels, which is required to initiate a P53-mediated cell cycle arrest and/or apoptosis. P53 and MDM-2 form a feedback control loop: while P53 can transactivate the MDM-2 gene, high levels of MDM-2 inhibit P53 transactivation as well as promote rapid degradation of P53. In the present study, we investigated the interaction between endogenous MDM-2 and P53 following UV-induced DNA damage in an MDM-2 overexpression cell line. A human osteosarcoma cell line (OsACL, which contains wild-type P53 and overexpresses MDM-2 protein) was used in this study. Here we show that following UV treatment, P53 levels increased in the OsACL cells despite the presence of high-level endogenous MDM-2; however, CAT assays using a P53 reporter system revealed that this P53 was transcriptionally inactive. Although P53 transactivation was inhibited, MDM-2 levels rose markedly following UV irradiation. Northern blot analysis revealed that the increase in MDM-2 protein levels was a result of increased levels of MDM-2 mRNA, possibly due to increased transcription. Cell cycle analysis revealed that OsACL cells were markedly resistant to UV-induced apoptosis. Transfection of OsACL cells with an anti-sense MDM-2 plasmid dowregulated MDM-2 expression and increased UV-induced apoptosis. In conclusion, MDM-2 overexpression can block UV-induced cell cycle arrest and apoptosis by inhibiting P53 transcriptional activity. Furthermore, increased expression of MDM-2 in OsACL cells following UV irradiation appears to be related to P53-independent mechanisms.
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PMID:Increased mdm-2 expression in a p53-independent manner blocks UV-induced cell cycle arrest and apoptosis in human osteosarcoma cells. 1461 Mar 16

Arsenic is a naturally occurring element, but anthropogenic activities can lead to a substantial contamination of the environment. Exposure to arsenic has been associated with a significant number of adverse health effects in humans including: cardiovascular disease, diabetes, hearing loss, developmental abnormalities, anemia, neurologic and neurobehavioral disorder, leukopenia, eosinophilia, fibrosis of the liver and the kidney and various neoplasms. However, the cellular and molecular events associated with arsenic toxicity are poorly understood. Also, the precise mechanisms by which arsenic acts as a carcinogen in humans remain to be elucidated. In the present study, we used human liver carcinoma (HepG2) cells as a model to study the molecular mechanisms of arsenic-induced toxicity and carcinogenesis. We hypothesized that arsenic-induced expression of stress genes and related proteins may play a role in the cellular and molecular events leading to toxicity and tumorigenesis in liver cells. To test this hypothesis, we performed the MTT-assay for cell viability, the CAT-Tox (L) assay for gene induction, and the Western Blot analysis to assess the expression of cellular proteins including c-fos, HMTIIA, HSP70 and p53. Data obtained from the MTT assay indicated a strong dose-response relationship with respect to arsenic trioxide toxicity. Upon 48 hr of exposure, the chemical dose required to cause 50% reduction in cell viability (LD50) was computed to be 8.55 +/- 0.58 microg/ml. The CAT-Tox (L) assay showed statistically significant inductions (p<0.05) of c-fos, HMTIIA, and HSP70. Western blot analysis also demonstrated a dose-response relationship with regard to expression of specific cellular proteins. The p53 protein was expressed in arsenic trioxide-treated cells, however, the densitometric analysis did not show any significant differences (p<0.05) between treated and control cells. The lack of a significant induction of p53 may be due to the potential mitogenic effect of arsenic at low levels of arsenic exposure.
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PMID:Arsenic trioxide-induced transcriptional activation of stress genes and expression of related proteins in human liver carcinoma cells (HepG2). 1468 89

A child with an unusual association of cancers is described. The patient first presented with a rhabdomyosarcoma of the right scapular muscle, and was successfully treated with chemotherapy. Six years after diagnosis of the first malignancy, the child presented with two synchronous malignancies: osteosarcoma of the jaw and adrenocortical carcinoma. Genetic mutation analysis was performed and revealed a germline p53 mutation of CGT > CAT at codon 273. The family history was negative for any other cancer consistent with the Li-Fraumeni syndrome. This case highlights the need for close surveillance of patients with p53 mutation for malignancy and describes the occurrence of two malignancies synchronously.
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PMID:Rhabdomyosarcoma, osteosarcoma, and adrenocortical carcinoma in a child with a germline p53 mutation. 1539 Feb 94

Exposing CGL1 (HeLa x fibroblast) hybrid cells to 7 Gy of X rays results in the onset of a delayed apoptosis in the progeny of the cells 10 to 12 cell divisions postirradiation that correlates with the emergence of neoplastically transformed foci. The delayed apoptosis begins around day 8 postirradiation and lasts for 11 days. We now demonstrate that the delayed apoptosis is also characterized by the appearance of approximately 50-kb apoptotic DNA fragments and caspase 3 activation postirradiation. In addition, we confirm that stabilization of TP53 and transactivation of pro-apoptosis BAX also occurs during the delayed apoptosis and show that anti-apoptosis BCL-X(L) is down-regulated. To test whether the delayed apoptosis was due to a nonfunctional acute TP53 damage response in CGL1 cells, studies of acute apoptosis were completed. After irradiation, CGL1 cells underwent an acute wave of apoptosis that involves TP53 stabilization, transactivation of BAX gene expression, and a rapid caspase activation that ends by 96 h postirradiation. In addition, the acute onset of apoptosis correlates with transactivation of a standard wild-type TP53-responsive reporter (pG13-CAT) in CGL1 cells after radiation exposure. We propose that the onset of the delayed apoptosis is not the result of a nonfunctional acute TP53 damage response pathway but rather is a consequence of X-ray-induced genomic instability arising in the distant progeny of the irradiated cells.
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PMID:A radiation-induced acute apoptosis involving TP53 and BAX precedes the delayed apoptosis and neoplastic transformation of CGL1 human hybrid cells. 1591 93

The reason why vulnerabilities to mutant polyglutamine (polyQ) proteins are different among neuronal subtypes is mostly unknown. In this study, we compared the gene expression profiles of three types of primary neurons expressing huntingtin (htt) or ataxin-1. We found that heat shock protein 70 (hsp70), a well known chaperone molecule protecting neurons in the polyQ pathology, was dramatically upregulated only by mutant htt and selectively in the granule cells of the cerebellum. Granule cells, which are insensitive to degeneration in the human Huntington's disease (HD) pathology, lost their resistance by suppressing hsp70 with siRNA, whereas cortical neurons, affected in human HD, gained resistance by overexpressing hsp70. This indicates that induction levels of hsp70 are a critical factor for determining vulnerabilities to mutant htt among neuronal subtypes. CAT (chloramphenicol acetyltransferase) assays showed that CBF (CCAAT box binding factor, CCAAT/enhancer binding protein zeta) activated, but p53 repressed transcription of the hsp70 gene in granule cells. Basal and mutant htt-induced expression levels of p53 were remarkably lower in granule cells than in cortical neurons, suggesting that different magnitudes of p53 are linked to distinct induction levels of hsp70. Surprisingly, however, heat shock factor 1 was not activated in granule cells by mutant htt. Collectively, different levels of hsp70 among neuronal subtypes might be involved in selective neuronal death in the HD pathology.
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PMID:The induction levels of heat shock protein 70 differentiate the vulnerabilities to mutant huntingtin among neuronal subtypes. 1725 28

To elucidate the regulatory mechanism of p73 gene expression, we analyzed the human p73 promoter and found three putative Egr-1-binding sites located upstream of exon 1 (-1728, -321, and -38). The Egr-1 responsiveness of these sites was analyzed by transient transfection assays using 5'- and 3'-serial truncations of the p73 promoter, subcloned in a CAT reporter vector. The functional significance of the region was further confirmed by an electrophoretic mobility shift assay using the Egr-1 protein synthesized in vitro and a [32P]-labeled middle site sequence, followed by competition with unlabeled wild-type or mutant oligonucleotides and supershift assays using an anti-Egr-1 antibody. When induced by either the nitric oxide donor NOC-18 or the PPARgamma agonist troglitazone, Egr-1 bound to the p73 promoter, as assessed by chromatin immunoprecipitation assays, accompanied by increased expression of p73. MTT assays revealed that cell growth was significantly inhibited on treating the cells with troglitazone. Overall, our results provide direct evidence that Egr-1 positively regulated p73 expression by binding to its promoter in vivo, consistent with Egr-1 and p73 being involved in p53-independent tumor suppression.
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PMID:Transcriptional regulation of the p73 gene, a member of the p53 family, by early growth response-1 (Egr-1). 1782 68

The tumor suppressor protein p53 triggers many of the cellular responses to DNA damage by regulating the transcription of a series of downstream target genes. p53 acts on the promoter of the target genes by interacting with the trimeric transcription factor NF-Y. H ferritin promoter activity is tightly dependent on a multiprotein complex called Bbf; on this complex NF-Y plays a major role. The aim of this work was to study the modulation of H ferritin expression levels by p53. CAT reporter assays indicate that: (i) p53 overexpression strongly downregulates the transcriptional efficiency driven by an H ferritin promoter construct containing only the NF-Y recognition sequence and that the phenomenon is reverted by p53 siRNA; (ii) the p53 C-terminal region is sufficient to elicitate this regulation and that a correct C-terminal acetylation is also required. The H ferritin promoter displays no p53-binding sites; chromatin immunoprecipitation assays indicate that p53 is recruited on this promoter by NF-Y. The p53-NF-Y interaction does not alter the NF-Y DNA-binding ability as indicated by electrophoretic mobility shift assay (EMSA) analysis. These results demonstrate that the gene coding for the H ferritin protein belongs to the family of p53-regulated genes, therefore adding a new level of complexity to the regulation of the H ferritin transcription and delineate a role for this protein in a series of cellular events triggered by p53 activation.
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PMID:p53-mediated downregulation of H ferritin promoter transcriptional efficiency via NF-Y. 1837 7

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent endocrine disruptor compound and induces multiple organ dysfunctions. The effect of TCDD exposure both in adults and in utero has been well established. However, little is known about the effects of TCDD acquired through mother's milk on the development of the male reproductive system. The aim of this study was to investigate the effects and mechanisms of TCDD from lactational exposure. TCDD (1 microg/kg) was administered to C57BL/6 mouse mothers for 4 days from the day of delivery. On postnatal day 30 (PND 30) and postnatal day 60 (PND 60), body weight, body length, and anogenital distance (AGD) of male offspring were measured. The weights of the testes and epididymides were also measured. Epididymides were used for sperm counts, and testes were used to measure the activity of antioxidant enzymes (SOD, CAT, GPX, GR), the parameters of oxidative stress (hydrogen peroxide, MDA), and testosterone. In addition, expression of p53 and the proapoptotic protein, Bax, were analyzed by Western blot. TCDD exposure decreased body weight, body length, and AGD in both PND 30 and PND 60 groups compared with the control group. The activity of all antioxidant enzymes at PND 60 was decreased after TCDD treatment. TCDD treatment decreased testicular testosterone levels in both the PND 30 and PND 60 groups. The expression of p53 and Bax were also upregulated by TCDD and did not return to normal levels by PND 60. These data suggest that TCDD affects development of male offspring when the mother is exposed to TCDD during lactation. In addition, oxidative stress is a major mediator of TCDD-induced adverse effects, and p53 may play an important role in this mechanism.
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PMID:Toxic effects of lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on development of male reproductive system: involvement of antioxidants, oxidants, and p53 protein. 1908 97

Mutations of the IDH1 gene are frequent in gliomas, with R132H (CGT-->CAT) being the most common (>85%). In astrocytomas, IDH1 mutations are typically co-present with, or precede, TP53 mutations. We assessed IDH1 mutations in brain tumors diagnosed in patients from three families with Li-Fraumeni syndrome. We identified IDH1 mutations in five astrocytomas that developed in carriers of a TP53 germline mutation. Without exception, all were R132C (CGT-->TGT), which in sporadic astrocytomas accounts for <5% of IDH1 mutations. This remarkably selective occurrence of R132C mutations may reflect differences in the sequence of genetic events, with a preference for R132C mutations in astrocytes or precursor cells that already carry a germline TP53 mutation.
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PMID:Selective acquisition of IDH1 R132C mutations in astrocytomas associated with Li-Fraumeni syndrome. 1934 Apr 32

Hepatitis B virus (HBV) may contribute to hepatocarcinogenesis by blocking p53 function. A p53 response element-like binding sequences, TGCCT...TGCCT, was found in HBV genome. To clarify whether HBV DNA can, like some other DNA viruses, bind to P53 protein and form a DNA-protein complex, we used a series of plasmids encoding full-length or mutant HBV or p53 fragments to determine the binding ability of HBV DNA after cotransfected into cells by electrophoretic mobility shift (and supershift) assay. We found that HBV DNA could bind to P53 protein and form DNA-protein complexes in human hepatoma cell lines. Cotransfection with p53 and HBV DNA increased the replication of HBV, CAT activity, tumor cell apoptosis, and cytoplasmic P53 accumulation in the hepatoma cells. In conclusions, our observations suggest that the interaction of HBV and p53 at the levels of protein-protein and DNA-protein, which resulted in inactivation of p53 transactivation.
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PMID:HBV DNA can bind to P53 protein and influence p53 transactivation in hepatoma cells. 1954 Jan 92


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