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)

Ataxia-telangiectasia (A-T) is a human disease characterized by high cancer risk, immune defects, radiation sensitivity, and genetic instability. Although A-T homozygotes are rare, the A-T gene may play a role in sporadic breast cancer and other common cancers. Abnormalities of DNA repair, genetic recombination, chromatin structure, and cell cycle checkpoint control have been proposed as the underlying defect in A-T; however, previous models cannot satisfactorily explain the pleiotropic A-T phenotype. Two recent observations help clarify the molecular pathology of A-T: (a) inappropriate p53-mediated apoptosis is the major cause of death in A-T cells irradiated in culture; and (b) ATM, the putative gene for A-T, has extensive homology to several cell cycle checkpoint genes from other organisms. Building on these new observations, a comprehensive model is presented in which the ATM gene plays a crucial role in a signal transduction network that activates multiple cellular functions in response to DNA damage. In this Damage Surveillance Network model, there is no intrinsic defect in the machinery of DNA repair in A-T homozygotes, but their lack of a functional ATM gene results in an inability to: (a) halt at multiple cell cycle checkpoints in response to DNA damage; (b) activate damage-inducible DNA repair; and (c) prevent the triggering of programmed cell death by spontaneous and induced DNA damage. Absence of damage-sensitive cell cycle checkpoints and damage-induced repair disrupts immune gene rearrangements and leads to genetic instability and cancer. Triggering of apoptosis by otherwise nonlethal DNA damage is primarily responsible for the radiation sensitivity of A-T homozygotes and results in an ongoing loss of cells, leading to cerebellar ataxia and neurological deterioration, as well as thymic atrophy, lymphocytopenia, and a paucity of germ cells. Experimental evidence supporting the Damage Surveillance Network model is summarized, followed by a discussion of how defects in the ATM-dependent signal transduction network might account for the A-T phenotype and what insights this new understanding of A-T can offer regarding DNA damage response networks, genomic instability, and cancer.
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PMID:Ataxia-telangiectasia and cellular responses to DNA damage. 852 80

'Checkpoint' controls arrest the cell cycle after DNA damage, allowing repair to take place before mutations can be perpetuated. In multicellular organisms, DNA damage can also induce apoptotic cell death, protecting the organism at the expense of the individual cell. How does a cell 'choose' between cycle arrest and death? Analysis of two human tumour suppressor proteins, p53 and the ATM (ataxia-telangiectasia mutated) gene product, may provide some answers.
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PMID:Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM. 853 57

A substantial proportion of patients with primary immunodeficiency diseases develop tumors, particularly those of lymphoreticular system caused by Epstein-Barr virus (EBV). Primary immunodeficiency renders patients susceptible to EBV by reducing immune reactions and surveillance abilities against the virus or inducing overreaction of the responding cells to the antigens. Recent progress in molecular biology has unraveled the genes responsible for several types of primary immunodeficiency diseases. The cloning of the ATM gene demonstrated that the mutations in this gene were observed in the members of all the families affected with ataxia telangiectasia (AT), indicating the crucial role of this gene in the pathogenesis of AT. The protein encoded by the ATM gene shows a high sequence homology with several proteins which are presumed to be involved in the regulation of the cell cycle transition. Accumulating evidence indicates that AT-derived cells are sensitive to irradiation due to the abnormalities in p53-dependent cell cycle arrest at G1 phase. Thus, the ATM product may regulate the cell cycle at G1 phase in a p53-dependent manner and the defect of the gene may lead to the accumulation of cells with DNA damages, thereby causing malignant transformation.
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PMID:[Primary immunodeficiency diseases]. 853 51

The DNA-dependent protein kinase (DNA-PK), whose catalytic subunit shows structural similarities to the Ataxia telangiectasia (AT) gene product (ATM), has also been implicated in the p53-mediated signal transduction pathway that activates the cellular response to DNA damage produced by ionizing radiation. DNA-PK activity however was not found to be related to the transcriptional induction of WAFl/CIP1(p2l) in AT lymphoblastoid cell lines, following treatment with ionizing radiation. Normal protein and transcription levels of Ku70 and Ku80, as well as DNA-PK activity, were found in six different AT cell lines, 1-4 h following exposure to ionizing radiation, timepoints where reduced and delayed transcriptional induction of WAF1/CIP1 (p21) was observed. WAF1/CIP1 (p21) was found to be transcriptionally induced by p53 in normal cell lines over this same time period following exposure to ionizing radiation. These results suggest that despite the findings that in vitro DNA-PK may phosphorylate p53, in vivo it would not appear to play a central role in the activation of p53 as a transcription factor nor can it substitute for the ATM gene product in the cellular response following exposure to ionizing radiation.
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PMID:The role of Ataxia telangiectasia and the DNA-dependent protein kinase in the p53-mediated cellular response to ionising radiation. 880 86

The gene mutated in ataxia-telangiectasia (AT) patients, denoted ATM, encodes a putative protein or lipid kinase. To elucidate the functions of ATM, we disrupted the mouse ATM gene through homologous recombination in mice. Consistent with cellular defects of AT patients, the ATM-/- cells are hypersensitive to gamma-irradiation and defective in cell-cycle arrest following radiation, correlating with a defective up-regulation of p53. In addition, ATM-/- mouse thymocytes are more resistant to apoptosis induced by gamma-irradiation than normal thymocytes. ATM-/- fibroblasts are inefficient in G1 to S-phase progression following serum stimulation and senesce after only a few passages in culture. They have an increased constitutive level of p21CP1/WAF1. The ATM protein is therefore critical both for cellular responses to ionizing radiation and for normal cell-cycle progression. ATM+/- fibroblasts and thymocytes showed intermediately defective responses to irradiation but no growth defect, suggesting that the increased cancer risk of AT heterozygotes could be attributable to poor checkpoint function.
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PMID:Dual roles of ATM in the cellular response to radiation and in cell growth control. 884 91

In response to DNA damage, cells transduce a signal that leads to accumulation and activation of p53 protein, transcriptional induction of several genes, including p21, gadd45, and gadd153, and cell cycle arrest. One hypothesis is that the signal is mediated by DNA-dependent protein kinase (DNA-PK), which consists of a catalytic subunit (DNA-PKcs) and a regulatory subunit (Ku). DNA-PK has several characteristics that support this hypothesis: Ku binds to DNA damaged by nicks or double-strand breaks, DNA-PKcs is activated when Ku binds to DNA, DNA-PK will phosphorylate p53 and other cell cycle regulatory proteins in vitro, and DNA-PKcs shares homology with ATM, which is mutated in ataxia telangiectasia and involved in signaling the p53 response to ionizing radiation. The hypothesis was tested by analyzing early passage fibroblasts from severe combined immunodeficient mice, which are deficient in DNA-PK. After exposure to ionizing radiation, UV radiation, or methyl methane-sulfonate, severe combined immunodeficient and wild-type cells were indistinguishable in their response. The accumulation of p53, induction of p21, gadd45, and gadd153, and arrest of the cell cycle in G1 and G2 occurred normally. Therefore, DNA-PK is not required for the p53 response or cell cycle arrest after DNA damage.
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PMID:DNA-dependent protein kinase is not required for accumulation of p53 or cell cycle arrest after DNA damage. 898 43

The product of the ataxia-telangiectasia gene (ATM) was identified by using an antiserum developed to a peptide corresponding to the deduced amino acid sequence. The ATM protein is a single, high-molecular weight protein predominantly confined to the nucleus of human fibroblasts, but is present in both nuclear and microsomal fractions from human lymphoblast cells and peripheral blood lymphocytes. ATM protein levels and localization remain constant throughout all stages of the cell cycle. Truncated ATM protein was not detected in lymphoblasts from ataxia-telangiectasia patients homozygous for mutations leading to premature protein termination. Exposure of normal human cells to gamma-irradiation and the radiomimetic drug neocarzinostatin had no effect on ATM protein levels, in contrast to a noted rise in p53 levels over the same time interval. These findings are consistent with a role for the ATM protein in ensuring the fidelity of DNA repair and cell cycle regulation following genome damage.
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PMID:The ataxia-telangiectasia gene product, a constitutively expressed nuclear protein that is not up-regulated following genome damage. 905 Aug 66

The development of a normal cell into a tumor cell appears to depend in part on mutations in genes that normally control cell cycle and cell death, thereby resulting in inappropriate cellular survival and tumorigenesis. ATM ("mutated in ataxia-telangiectasia") and p53 are two gene products that are believed to play a major role in maintaining the integrity of the genome such that alterations in these gene products may contribute to increased incidence of genomic changes such as deletions, translocations, and amplifications, which are common during oncogenesis. p53 is a critical participant in a signal transduction pathway that mediates either a G1 arrest or apoptosis in response to DNA damage. In addition, p53 is believed to be involved in the mitotic spindle checkpoint and in the regulation of centrosome function. Following certain cytotoxic stresses, normal ATM function is required for p53-mediated G1 arrest. ATM is also involved in other cellular processes such as S phase and G2-M phase arrest and in radiosensitivity. The understanding of the roles that both p53 and ATM play in cell cycle progression and cell death in response to DNA damage may provide new insights into the molecular mechanisms of cellular transformation and may help identify potential targets for improved cancer therapies.
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PMID:p53 and ATM: cell cycle, cell death, and cancer. 911 62

The recently cloned gene (ATM) mutated in the human genetic disorder ataxia-telangiectasia (A-T) is involved in DNA damage response at different cell cycle checkpoints and also appears to have a wider role in signal transduction. Antibodies prepared against peptides from the predicted protein sequence detected a approximately 350 kDa protein corresponding to the open reading frame, which was absent in 13/23 A-T homozygotes. Subcellular fractionation, immunoelectronmicroscopy and immunofluorescence showed that the ATM protein is present in the nucleus and cytoplasmic vesicles. This distribution did not change after irradiation. We also provide evidence that ATM protein binds to p53 and this association is defective in A-T cells compatible with the defective p53 response in these cells. These results provide further support for a role for the ATM protein as a sensor of DNA damage and in a more general role in cell signalling, compatible with the broader phenotype of the syndrome.
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PMID:Cellular localisation of the ataxia-telangiectasia (ATM) gene product and discrimination between mutated and normal forms. 915 Mar 58

Studies of the roles of oncoproteins in cell cycle progression have concentrated on G1 because transformation is frequently associated with loss of G1 checkpoint control. However, it has become evident that G2 and mitotic checkpoints are often compromised in transformed cells and that many tumour suppressor proteins and oncoprotein kinases regulate and/or are activated in G2 and M. Disruption of p53 and ATM tumour suppressor protein functions can eliminate G2 and M checkpoints. The Src family kinases are activated in mitosis and collectively play an indispensable role in progression through G2/M. In addition, evidence suggests that Mos and elements of the Ras/Raf/MAPK cascade are also active in mitosis and appear likely to regulate G2 and/or M. Potential targets of these kinases include likely regulators of gene expression and microtubule dynamics such as Sam68 and Oncoprotein 18/stathmin. The ability of some oncoproteins to perturb orderly progression through both G1 and/or S and G2 and/or M is probably important for transformation.
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PMID:Oncoprotein signalling and mitosis. 921 24


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