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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 tumour suppressor gene is the most widely mutated gene in human tumorigenesis. p53 encodes a transcriptional activator whose targets may include genes that regulate genomic stability, the cellular response to DNA damage, and cell-cycle progression. Introduction of wild-type p53 into cell lines that have lost endogenous p53 function can cause growth arrest or induce a process of cell death known as apoptosis. During normal development, self-reactive thymocytes undergo negative selection by apoptosis, which can also be induced in immature thymocytes by other stimuli, including exposure to glucocorticoids and ionizing radiation. Although normal negative selection involves signalling through the T-cell receptor, the induction of apoptosis by other stimuli is poorly understood. We have investigated the requirement for p53 during apoptosis in mouse thymocytes. We report here that immature thymocytes lacking p53 die normally when exposed to compounds that may mimic T-cell receptor engagement and to glucocorticoids but are resistant to the lethal effects of ionizing radiation. These results demonstrate that p53 is required for radiation-induced cell death in the thymus but is not necessary for all forms of apoptosis.
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PMID:p53 is required for radiation-induced apoptosis in mouse thymocytes. 847 14

Death by apoptosis is characteristic of cells undergoing deletion during embryonic development, T- and B-cell maturation and endocrine-induced atrophy. Apoptosis can be initiated by various agents and may be a result of expression of the oncosuppressor gene p53 (refs 6-8). Here we study the dependence of apoptosis on p53 expression in cells from the thymus cortex. Short-term thymocyte cultures were prepared from mice constitutively heterozygous or homozygous for a deletion in the p53 gene introduced into the germ line after gene targeting. Wild-type thymocytes readily undergo apoptosis after treatment with ionizing radiation, the glucocorticoid methylprednisolone, or etoposide (an inhibitor of topoisomerase II), or after Ca(2+)-dependent activation by phorbol ester and a calcium ionophore. In contrast, homozygous null p53 thymocytes are resistant to induction of apoptosis by radiation or etoposide, but retain normal sensitivity to glucocorticoid and calcium. The time-dependent apoptosis that occurs in untreated cultures is unaffected by p53 status. Cells heterozygous for p53 deletion are partially resistant to radiation and etoposide. Our results show that p53 exerts a significant and dose-dependent effect in the initiation of apoptosis, but only when it is induced by agents that cause DNA-strand breakage.
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PMID:Thymocyte apoptosis induced by p53-dependent and independent pathways. 847 14

We describe the isolation and characterization of cDNAs encoding full-length human and murine cyclin G1 and a novel human homologue of this cyclin designated cyclin G2. Cyclin G1 is expressed at high levels in skeletal muscle, ovary, and kidney. Following an initial up-regulation from early G1 to G1/S phase, cyclin G1 mRNA is constitutively expressed throughout the cell cycle in T and B cell lines. In contrast, in stimulated peripheral T cells, cyclin G1 mRNA is maximal in early G1 phase and declines in cell cycle progression. Cyclin G1 levels parallel p53 expression in murine B lymphocytes; however, in several human Burkitt's lymphomas, murine lymphocytes treated with transforming growth factor-beta, early murine embryos, and several tissues of p53 null mice, cyclin G1 levels are either inverse of p53 levels or expressed independent of p53. The cyclin G1 homologue, cyclin G2, exhibits 60% nucleotide sequence identity and 53% amino acid sequence identity with cyclin G1, and like cyclin G1, exhibits closest sequence identity to the cyclin A family. Distinct from cyclin G1, the amino acid sequence for cyclin G2 shows a PEST-rich sequence and a potential Shc PTB binding site. Cyclin G2 mRNA is differentially expressed compared to cyclin G1, the highest transcript levels seen in cerebellum, thymus, spleen, prostate, and kidney. In contrast to the constitutive expression of cyclin G1 in lymphocytes, cyclin G2 mRNA appears to oscillate through the cell cycle with peak expression in late S phase.
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PMID:Cyclin G1 and cyclin G2 comprise a new family of cyclins with contrasting tissue-specific and cell cycle-regulated expression. 862 90

In order to search for the direct evidence of cellular response to low-dose radiation, we investigated wild-type p53 protein accumulation in several organs of mice after exposure to low doses of X-rays. Significant p53 accumulation within 24 h was observed in the mouse adrenal glands and pancreas after X-ray irradiation at 25 cGy and 50 cGy, but not at 100 cGy. In addition, differential p53 accumulation was also observed in the hypophysis, thymus, skin, lung, bone marrow and liver at different doses. In contrast, we observed no accumulation of p53 protein in the spleen, testis or kidney at any dose used in this experiment. The p53 accumulation induced by low-dose X-rays in mice was organ-specific. It is suggested that cell type and interactions with other signal transduction pathways of the hormone system, immune system and/or nervous system may contribute to the variable induction of p53 by low-dose X-ray irradiation. The association of organ-specific p53 response with radiosensitivity and cancer incidence by radiation in each organ was discussed.
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PMID:p53 accumulation in the organs of low-dose X-ray-irradiated mice. 864 Jul 50

Binding of simian virus 40 (SV40) large T antigen to human and calf thymus topoisomerase I (topo I) was readily detected by using modified enzyme-linked immunosorbent assays and immunoblots. In addition to WT T antigen, binding could also be readily demonstrated with T antigen fragments from the amino-terminal region as well as with fragments missing this region, but much less so with small t antigen or with human p53. Antibody-blocking experiments showed that a monoclonal antibody that binds to the N-terminal region and several antibodies that recognize the central region of T antigen interfere with the binding to topo I. Our data are consistent with the existence of two separate topo I-binding regions in T antigen, one mapping within residues 82 to 246 and an apparently weaker one present after residue 246. By comparing the binding of T antigen to topo I with that of T antigen to DNA polymerase alpha or RPA, a single-stranded DNA-binding protein, it was determined that the T antigen-topo I interaction is much stronger and that the binding sites for topo I and DNA polymerase overlap, whereas the one for RPA differs. Several unwinding-defective mutants of T antigen were partially defective in their binding to topo I, suggesting that the binding to topo I is required for unwinding circular DNA. Finally, immunoprecipitation experiments demonstrated that T antigen can interact with DNA-bound topo I, indicating that such an interaction may take place during SV40 DNA replication.
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PMID:Simian virus 40 large T antigen binds to topoisomerase I. 880 20

The role of the p53 tumor suppressor gene in bovine lymphosarcomas, a fragment of about 100 bp corresponding to approximately 97% of the open reading frame of the p53 gene was first amplified from single-strand cDNA originated from calf thymus by polymerase chain reaction PCR) and sequenced to obtain the bovine wild-type p53 gene. At the amino acid level, the omologies of the bovine p53 gene with the human, mouse, chicken and cat p53 genes were 0.9%, 72.8%, 52.7% and 82.3%, respectively. Moreover, eight bovine leukemic cells lines were studied for alterations in the p53 gene. These lines showed no significant somatic alterations in southern blot analysis, and expressed 2.5 kb p53-specific transcripts in Northern blot analysis. In mutation analysis using the reverse transcriptase-PCR technique, we detected three missense point mutations in four of these bovine leukemic cell lines. These mutations occurred in the 'hotspots' of the p53 gene. Thus p53 mutations predominantly occur in BLV-transformed cell lines and seem to be necessary for development of enzootic bovine leukosis (EBL).
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PMID:Predominant p53 mutations in enzootic bovine leukemic cell lines. 880 76

2',3'-dideoxycytidine (ddC) is a synthetic pyrimidine nucleoside analogue approved for treatment of HIV-positive patients. Previous studies indicated that ddC has the potential to cause thymic lymphoma in C57BL/6 x C3H F1 (hereafter called B6C3F1) mice. In this study, we evaluated the carcinogenic potential of ddC in two different mouse models. B6C3F1 hybrid mice carry ecotropic endogenous proviral sequences that may be activated to cause lymphoma, whereas NIH Swiss mice lack proviral sequences that can be expressed. The mice were treated with ddC by gavage at 500 and 1000 mg/kg/day for up to 6 months (human dose, 2.25 mg/day) and evaluated for toxicity, plasma levels of ddC, and pathological changes. Lymphocyte cell markers from the thymic lymphomas were assessed by immunophenotyping. Expression of p53 protein was evaluated using immunohistochemical staining. Treatment-related thymic lymphomas were present in both mouse models with a higher incidence in NIH Swiss than in B6C3F1 mice. The lymphomas were more prevalent in females than in males of both mouse models. Most mice with thymic lymphoma died during the course of the study. In addition to the thymus, lymphoma was often present in lymph nodes, spleen, and other organs. Lymphomas arose more frequently in mice that lack endogenous ecotropic retroviral sequences and thus were not due to activation of endogenous provirus. During the third month of the study, a few NIH Swiss mice that died had granulosa cell tumors of the ovary. Treatment-related but reversible thymic atrophy was observed in both mouse models. There was a very high correlation between the internal dose of ddC and the incidence of thymic lymphoma in both mouse models. Most of the lymphocytes from control thymuses and ddC-induced lymphomas were positive for Thy-1.2 (pan-T), heat stable antigen, and CD4 and CD8 markers, with no marked differences in the lymphocyte markers of the tumors between sexes or dose groups. p53 protein was detected in only 20% (23/115) of the ddC-induced lymphomas with mostly minimal expression in scattered cells. Because ddC induced lymphomas in two different mouse models, the potential carcinogenic risk should be considered in long-term treatment of HIV-positive patients, especially children and adolescent patients treated with ddC.
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PMID:Carcinogenicity of 2',3'-dideoxycytidine in mice. 884 Sep 82

Apoptosis of normal thymocytes was shown to be triggered by several mechanisms (e.g. glucocorticoids, gamma-irradiation). In the present study the authors report on thymocyte apoptosis that is induced by thymic epithelial cells. The thymocytes undergo a massive apoptotic death within 24 h of cocultivation with thymic epithelial cell monolayers derived from primary cultures (PTEC) or from a thymic epithelial cell line (TEC). Non-thymic monolayers were inactive. Apoptosis induction in this experimental model requires direct contact between the thymocytes and the thymic epithelial monolayer and can be blocked by anti-CD2 and anti-LFA-1 antibodies. The immature CD3-/+dull CD4+CD8+ thymocytes were the cells which undergo apoptosis. The fact that the authors are dealing with a massive apoptotic process of immature cells in the absence of exogenous antigen suggests that it involves the nonselected thymocytes. The apoptotic pathway selected by thymocytes following their culturing on TEC involves p53 expression. Indeed it was found that TEC-induced apoptosis, led to the accumulation of p53 protein that preceded the step of DNA fragmentation in freshly isolated thymocytes as well as in a glucocorticoid resistant thymoma cell line. Since glucocorticoid-induced thymocyte apoptosis is p53-independent, glucocorticoids are conceivably not involved in TEC-induced thymocyte death. The in vitro experimental model presented here may reflect the physiological sequence of events leading to thymocyte death in the thymus.
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PMID:Induction of apoptosis and p53 expression in immature thymocytes by direct interaction with thymic epithelial cells. 884 23

Apoptosis in the immature thymus can be induced by both p53-dependent and -independent pathways, the former being activated by exposure to DNA-damaging agents and the latter being induced by glucocorticoids [Nature (Lond.) 362:847-849; Nature (Lond.) 362:849-852 (1993)]. We report that the DNA-damaging agents etoposide and gamma-radiation induced similar levels of apoptosis in both proliferatively enriched and quiescent immature rat thymocytes, as assessed by flow cytometry and the formation of both kilobase-pair and 180-bp integer fragments of DNA. However, a marked stabilization of p53 occurred exclusively in the proliferatively enriched population, which was also enriched for immature CD4- CD8- and mature CD4+ CD8-/CD4- CD8+ cells. In contrast, DNA damage-induced apoptosis in quiescent mature peripheral T cells was associated with an accumulation of p53. Our studies suggest that stabilization of p53 in thymocytes in response to DNA damage may be developmentally regulated. In immature thymocytes obtained from p53-null mice, DNA-damaging agents induced apoptosis at significantly lower levels and at later times than that seen in cells from p53 wild-type animals. These data support the hypothesis that DNA-damaging agents induce apoptosis primarily via a p53-dependent pathway in immature thymocytes as previously reported. We report here that DNA damage can also induce apoptosis by a p53-independent pathway in a particular subpopulation of immature thymocytes.
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PMID:DNA-damaging agents induce both p53-dependent and p53-independent apoptosis in immature thymocytes. 886 36

p53 (-/-), lacI (+/-) double transgenic (p53/Big Blue3) mice provide an opportunity to examine the relationship in vivo between somatic mutation and tumorigenesis. Previously, the frequency and spectra of lacI mutations were found to be similar in normal tissues of 6 week old p53 (-/-) lacI (+/-) and p53 (+/+) lacI (+/-) mice. Herein, p53 (-/-), lacI (+/-) mice were used to examine the frequency and spectrum of spontaneous mutation in thymic lymphomas. Four mice with thymic lymphomas were sacrificed at 2.5, 3, 4 and 4.5 months of age. Normal thymus harvested from two p53 (+/+) lacI (+/-) mice and two p53 (-/-) lacI (+/-) mice served as controls. The mutation frequency in tumor 108 (6.8 x 10(-5)) was elevated 2.3-fold relative to the p53 (-/-) control (P<0.0001; chi2 test). The mutation spectra were also different (P=0.0009; Fisher exact test); in particular, A:T-->G:C transitions were prominently overrepresented in tumor 108. In addition, there were two examples of unusual deletions with inversions. In tumors 44 and 115, but not 110, there were trends toward increased mutation frequencies and altered spectra, but, within the constraints of present sample sizes, the results are not statistically significant. In conclusion, these findings suggest that altered frequencies and spectra exist in a subset of thymic lymphomas, perhaps due to somatic mutation in one or more DNA repair genes.
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PMID:Increased mutation frequency and altered spectrum in one of four thymic lymphomas derived from tumor prone p53/Big Blue double transgenic mice. 895 82


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