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)

Cytogenetic analysis of small lymphocytes disorders is hindered by the low mitotic activity of the malignant cells. The use of fluorescence in situ hybridization (FISH) allows the detection of chromosomal amplifications, deletions, or translocations at a single-cell level in dividing and resting cells. The use of FISH in combination with other molecular techniques has defined the deletion in band 13q14 as the most common abnormality in chronic lymphocytic leukemia, followed by del (11)(q22-23), trisomy 12, del (17)(p13), and del (6)(q21). The del 13q14 is also found in 70% of mantle-cell lymphomas (MCLs) and in non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) patients. These findings point to the existence of yet unidentified tumor-suppressor gene(s) at the 13q14 locus, the loss/inactivation of which leads to B-cell neoplasia. Del (17(p13) (involving the p53 tumor-suppressor gene) and del (11)(q22-23) (involving the ataxia-telangiectasia gene [ATM]) seem to be independent prognostic factors for poor survival in chronic lymphocytic leukemia (CLL) patients. In MCL, the t(11;14) involving the bcl-1 gene is found, but data from a bcl-1 transgenic animal model suggest that hyperexpression of bcl-1 is not sufficient for lymphomatogenesis. Similar data are observed in bcl-2 transgenic animals, a finding showing that the bcl-2 hyperexpression observed in t(14;18)-positive follicular lymphoma cells is not sufficient to confer a malignant phenotype. The contribution of other chromosomal abnormalities other than bcl-1 and bcl-2 rearrangements in the pathogenesis of MCL and follicular-cell lymphomas has to be determined.
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PMID:Genetics of small lymphocyte disorders. 1031 86

Cells lacking an intact ATM gene are hypersensitive to ionizing radiation and show multiple defects in the cell cycle-coupled checkpoints. DNA damage usually triggers cell cycle arrest through, among other things, the activation of p53. Another DNA-damage responsive factor is NF-kappaB. It is activated by various stress situations, including oxidative stress, and by DNA-damaging compounds such as topoisomerase poisons. We found that cells from Ataxia Telangiectasia patients exhibit a defect in NF-kappaB activation in response to treatment with camptothecin, a topoisomerase I poison. In AT cells, this activation is shortened or suppressed, compared to that observed in normal cells. Ectopic expression of the ATM protein in AT cells increases the activation of NF-kappaB in response to camptothecin. MO59J glioblastoma cells that do not express the DNA-PK catalytic subunit respond normally to camptothecin. These results support the hypothesis that NF-kappaB is a DNA damage-responsive transcription factor and that its activation pathway by DNA damage shares some components with the one leading to p53 activation.
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PMID:The ATM protein is required for sustained activation of NF-kappaB following DNA damage. 1032 72

The genetic determinants for most breast cancer cases remain elusive. However, a mutation in a tumor suppressor gene, such as p53, BRCA1, BRCA2, or ATM, has been determined to be one mechanism of breast carcinogenesis. It has been established that inherited mutations in p53, BRCA1, and BRCA2 significantly contribute to breast cancer risk, although the importance of an inherited ATM mutation is controversial. Sporadic mutations in p53 are also common in breast cancer cells. The precise deficiencies that result from these genetic mutations have yet to be fully described. Although the functions of these genes are different, they are all involved in the maintenance of genomic stability after DNA damage. Mutations that impair the function of these four genes may adversely affect the manner in which DNA damage is processed. It is likely that the risk of breast cancer development is increased through this mechanism. In this article, we review the relevancy of p53, BRCA1, BRCA2, and ATM mutations to breast cancer development, and review the in vitro, in vivo, and clinical data exploring the mechanisms by which these mutations affect genomic integrity and DNA damage repair.
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PMID:Tumor suppressor genes and breast cancer. 1033 46

Ionizing radiation-induced stabilization and the resultant transient accumulation of the p53 tumor suppressor protein is impaired in cells from ataxia telangiectasia (AT) patients, indicating a key role for ATM, the gene mutated in AT, upstream in the radiation-responsive p53 signaling pathway. Activation of this pathway is generally assumed to be triggered by DNA strand breaks produced directly following genotoxic stress or indirectly during excision repair of DNA lesions. The aim of this study was to identify the triggering signal for induction of p53 in diploid human dermal fibroblasts treated with 4-nitroquinoline 1-oxide (4NQO), a model environmental carcinogen that produces both DNA strand breaks (like ionizing radiation) and alkali-stable bulky DNA lesions (like UV light). 4NQO treatment of fibroblasts cultured from normal and AT donors and those from patients with the UV-hypersensitivity disorder xeroderma pigmentosum (XP, complementation groups A, E and G) resulted in up-regulation of p53 protein. In normal fibroblasts, there was no temporal relationship between the incidence of DNA strand breaks and levels of p53 protein; >90% of strand breaks and alkali-labile sites were repaired over 2 h following treatment with 1 microM 4NQO, whereas approximately 3 h of post-treatment incubation was required to demonstrate a significant rise in p53 protein. In contrast, exposure of normal fibroblasts to gamma-rays resulted in a rapid up-regulation of p53 and the level peaked at 2 h post-irradiation. XP cells with a severe deficiency in the nucleotide excision repair pathway showed abnormally high levels of p53 protein in response to 4NQO treatment, indicating that lesions other than incision-associated DNA strand breaks trigger p53 up-regulation. We observed a consistent, inverse correlation between the ability of the various fibroblast cultures to induce p53 following 4NQO treatment and their DNA repair efficiencies. Treatment with 0.12 microM 4NQO, for example, caused a >2-fold up-regulation of p53 in excision repair-deficient (AT, XPA and XPG) strains without eliciting any effect on p53 levels in repair-proficient (normal and XPE) strains. We conclude that up-regulation of p53 by 4NQO is mediated solely by an ATM-independent mechanism and that the p53 response is primarily triggered by persistent alkali-stable 4NQO-DNA adducts.
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PMID:Inverse correlation between p53 protein levels and DNA repair efficiency in human fibroblast strains treated with 4-nitroquinoline 1-oxide: evidence that lesions other than DNA strand breaks trigger the p53 response. 1035 71

Previous studies have demonstrated that the pathological features of breast cancer are more aggressive in younger women than in their older counterparts, and that young age may be an independent marker for adverse prognosis. These findings have raised the question whether these differences are also present at the molecular level. In order to characterize the genetic alterations associated with early-onset breast cancer, 102 cases selected for age under 37 at diagnosis were examined for loss of heterozygosity (LOH) at nine different loci on chromosomes 11, 13 and 17. Ninety cases (88%), exhibited LOH for at least one marker. The D17S855 marker, intragenic in the BRCA1 gene, showed a high proportion of LOH (63%), whereas the intragenic marker for the TP53 gene, HP53, exhibited LOH in 43% of the cases. On chromosome 11, frequencies of LOH peaked at the D11S969 and D11S387 markers, which expressed LOH in 53% and 48% of the informative cases, whereas D11S1818, which is proximate to the ATM gene, exhibited an LOH frequency of 24%. A statistically significant correlation was found between LOH at the D11S387 marker and poor survival (P = 0.028). No such correlation was found for the adjacent D11S969 marker, located approximately 500 kb centromeric to D11S387. We conclude that one or more as yet unidentified genes, situated in chromosome bands 11q24.1-q25, could be involved in the initiation and/or progression of breast cancer in younger women.
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PMID:Frequent allelic losses at 11q24.1-q25 in young women with breast cancer: association with poor survival. 1036 Jun 64

To investigate the mechanism by which presenilin (PS) overexpression induces apoptosis, we studied the effects of these proteins on cell cycle progression. Transiently transfected HeLa cells were bromodeoxyuridine (BrdU) labeled to visualize DNA synthesis by immunofluorescence and stained with propidium iodide to measure DNA content by fluorescence-activated cell sorting (FACS). BrdU labeling was decreased in cells expressing presenilin-1 (PS1), presenilin-2 (PS2), an Alzheimer's disease-associated missense mutation PS2(N141I), and the carboxyl-terminally deleted PS2 construct PS2(166aa), compared with mock and neurofilament-light (NF-L) transfected cells. Analysis of BrdU incorporation in mitotically synchronized HeLa cells suggested that cells were arresting in the G1 phase of the cell cycle, and this was confirmed by FACS analysis. Interestingly, cell cycle progression was more inhibited by the expression of PS2(N141I) compared with wild-type PS2. In addition, ATM, the gene product mutated in ataxia-telangiectasia, does not appear to be a downstream effector of PS-induced cell cycle arrest as transfection of PS constructs into an ataxia-telangiectasia cell line also resulted in cell cycle inhibition. Quantitative immunoblotting of whole-cell lysates from PS-transfected cells did not reveal increases or decreases in the steady-state levels of p21, p27, p53, pRb, or c-myc, suggesting that the presenilins mediate cell cycle arrest by mechanisms other than simple changes in the steady-state levels of these cell-cycle-related proteins.
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PMID:Presenilin overexpression arrests cells in the G1 phase of the cell cycle. Arrest potentiated by the Alzheimer's disease PS2(N141I)mutant. 1039 46

ATW8 was a unique opportunity to review the complex and growing field of ataxia-telangiectasia (A-T) research and to cross-fertilize ideas for new experimental designs. A-T biology now encompasses human and mouse neurology, neurobiology, immunology, radiobiology, cell signalling, cell cycle checkpoints, gametogenesis, and oncogenesis, as well as radiotherapy, cancer epidemiology, premature aging, cytogenetics, and DNA repair mechanisms. By an as yet undetermined mechanism, the ATM protein appears to sense double strand breaks (DSB) during meiosis or mitosis, or breaks consequent to the damage of free radicals which are generated during the metabolism of food. As a protein kinase, ATM then directly phosphorylates p53 and interacts with many other molecules involved in homologous and nonhomologous DSB repair, as well as in cell signalling. Some of these molecule targets include: c-abl, ATR, chk-1, chk-2, RPA, BRCA1, BRCA2, NFkappaB/IkappaB alpha, beta-adaptin, and perhaps ATM itself. Thus, ATM is a "hierarchical kinase," initiating many pathways simultaneously. Parallel sessions or longer meetings will clearly be necessary for future A-T workshops.
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PMID:Eighth International Workshop on Ataxia-Telangiectasia (ATW8). 1044 4

The activation of the cysteine proteases with aspartate specificity, termed caspases, is of fundamental importance for the execution of programmed cell death. These proteases are highly specific in their action and activate or inhibit a variety of key protein molecules in the cell. Here, we study the effect of apoptosis on the integrity of two proteins that have critical roles in DNA damage signalling, cell cycle checkpoint controls, and genome maintenance-the product of the gene defective in ataxia telangiectasia, ATM, and the related protein ATR. We find that ATM but not ATR is specifically cleaved in cells induced to undergo apoptosis by a variety of stimuli. We establish that ATM cleavage in vivo is dependent on caspases, reveal that ATM is an efficient substrate for caspase 3 but not caspase 6 in vitro, and show that the in vitro caspase 3 cleavage pattern mirrors that in cells undergoing apoptosis. Strikingly, apoptotic cleavage of ATM in vivo abrogates its protein kinase activity against p53 but has no apparent effect on the DNA binding properties of ATM. These data suggest that the cleavage of ATM during apoptosis generates a kinase-inactive protein that acts, through its DNA binding ability, in a trans-dominant-negative fashion to prevent DNA repair and DNA damage signalling.
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PMID:Cleavage and inactivation of ATM during apoptosis. 1045 55

The product of the ATM gene, which is mutated in ataxia telangiectasia, is a nuclear phosphoprotein, and it involves the activation of the p53 pathway after ionizing radiation. Here we show that the ATM protein is constitutively associated with double strand DNA and that the interaction increases when the DNA is exposed to ionizing radiation. The ATM protein also had affinity to restriction endonuclease PvuII-digested DNA, but not to UV-irradiated DNA nor X-irradiated single-stranded DNA. The immunoprecipitation experiment detected very weak association between ATM and DNA-PK proteins, and immunodepletion of DNA-PK showed little or no effect on the interaction of the ATM protein with damaged DNA, indicating that an interaction with DNA-PK might not be required for the recruitment of the ATM protein to damaged DNA. Furthermore, the association was also confirmed in xrs-5 and xrs-6e cells, which are Chinese hamster ovary mutant cell lines defective in Ku80 function. These results indicate that the ATM protein is recruited to the site of DNA damage and it recognizes double strand breaks by itself or through an association with other DNA-binding protein other than DNA-PK and Ku80 proteins.
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PMID:Recruitment of ATM protein to double strand DNA irradiated with ionizing radiation. 1046 90

Patients with the human genetic disorder ataxia-telangiectasia (A-T) are characterized by immunodeficiency and a predisposition to develop lymphoid malignancies. The gene mutated in A-T patients, ATM, codes for a high molecular weight protein that is implicated in DNA damage recognition and cell cycle control. The ATM protein does not change in amount or cellular distribution throughout the cell cycle or in response to DNA damaging agents. Because peripheral blood mononuclear cells (PBMCs) are largely in a state of quiescence and can be readily stimulated to enter a proliferative phase and because A-T cells exhibit growth abnormalities and senescence, indicative of a general intracellular defect in signalling, we chose PBMCs to examine the relationship of ATM to the proliferative status of the cell. We show here that ATM protein is present at low levels in freshly isolated PBMCs and increases approximately 6-fold to 10-fold in response to a mitogenic stimulus, reaching a maximum after 3 to 4 days. A similar, but delayed response, was evident in the presence of serum only. This increase in ATM protein was accompanied by an increase in ATM kinase activity. While expression of ATM protein increased during proliferation, ATM mRNA expression was unchanged in stimulated and unstimulated cells and there was no evidence for increased ATM protein stability in the phytohemagglutinin (PHA)-treated cells. In keeping with the reduced levels of ATM in quiescent cells, the extent of radiation-induction of the p53 pathway was significantly lower than in mitogen-stimulated cells. Basal levels of p21 were elevated in quiescent cells, and the response to radiation was negligible or reduced compared with proliferating cells over a 2-hour period. Overall, the data suggest that the increase in ATM protein in proliferating cells is due to posttranscriptional regulation and points to a role for ATM in more general signalling.
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PMID:ATM is upregulated during the mitogenic response in peripheral blood mononuclear cells. 1047 29


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