Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The functionality of the p53-mediated pathway, activated in response to DNA damage, has been assessed in primary fibroblast cell cultures and Epstein-Barr virus-transformed lymphoblastoid cell lines derived from Nijmegen breakage syndrome (NBS) patients. This autosomal recessive disease is characterized by microcephaly, growth and mental retardation, chromosomal instability, radiosensitivity, and high cancer incidence. The recent mapping of the NBS gene to chromosome 8q21 demonstrates that NBS is genetically distinct from ataxia telangiectasia (AT). Changes in p53 protein levels were significantly reduced and delayed in all the NBS fibroblast cell cultures and lymphoblastoid cell lines examined compared to normal cultures over a 4-h period postirradiation (5 Gy). The transcriptional activation of p21(WAF1/CIP1) mRNA was also lower in 12 NBS fibroblast cultures examined. In agreement with an abrogated p53 function, NBS cells exposed to ionizing radiation show an abnormal cell cycle arrest at G1-S and a prolonged accumulation of cells in the G2 phase. In contrast, exposure to the alkylating agent methyl methanesulfonate results in similar increases of p53 and p21(WAF1/CIP1) mRNA in both cell types. The ATM gene transcript was found to be expressed at similar levels in NBS and normal cells, whereas it was strongly reduced in the AT homozygote cells examined. These results suggest that the ATM gene product cannot substitute for that of the NBS gene in the signaling of cellular damage produced by ionizing radiation and that both are involved in the activation of p53. The suboptimal p53-mediated response could contribute to the high cancer risk and radiosensitivity seen in NBS patients.
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PMID:Nijmegen breakage syndrome cells fail to induce the p53-mediated DNA damage response following exposure to ionizing radiation. 927 79

Gene mutations provide valuable clues to cellular metabolism. In humans such insights come mainly from genetic disorders. Ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are two distinct but closely related, single gene disorders that highlight a complex junction of several signal transduction pathways. These pathways appear to control defense mechanisms against specific types of damage to cellular macromolecules, and probably regulate the processing of certain types of DNA damage or normal intermediates of DNA metabolism. A-T is characterized primarily by cerebellar degeneration, immunodeficiency, genome instability, clinical radiosensitivity, and cancer predisposition. NBS shares all these features except cerebellar deterioration. The cellular phenotypes of A-T and NBS are almost indistinguishable, however, and include chromosomal instability, radiosensitivity, and defects in cell cycle checkpoints normally induced by ionizing radiation. The recent identification of the gene responsible for A-T, ATM, has revealed its product to be a large, constitutively expressed phosphoprotein with a carboxy-terminal region similar to the catalytic domain of phosphatidylinositol 3-kinases (PI 3-kinases). ATM is a member of a family of proteins identified in various organisms, which share the PI 3-kinase domain and are involved in regulation of cell cycle progression and response to genotoxic agents. Some of these proteins, most notably the DNA-dependent protein kinase, have an associated protein kinase activity, and preliminary data indicate this activity in ATM as well. Mutations in A-T patients are null alleles that truncate or destabilize the ATM protein. Atm-deficient mice recapitulate the human phenotype with slower nervous-system degeneration. Two ATM interactors, c-Abl and p53, underscore its role in cellular responses to genotoxic stress. The complexity of ATM's structure and mode of action make it a paradigm of multifaceted signal transduction proteins involved in many physiological pathways via multiple protein-protein interactions. The as yet unknown NBS protein may be a component in an ATM-based complex, with a key role in sensing and processing specific DNA damage or intermediates and signaling their presence to the cell cycle machinery.
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PMID:Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. 944 10

p53-mediated signal transduction after exposure to ionizing radiation was examined in cells from patients with Nijmegen breakage syndrome (NBS), an autosomal recessive disease characterized by microcephaly, immunodeficiency, predisposition to malignancy, and a high sensitivity to ionizing radiation. NBS cells accumulated p53 protein in a dose-dependent fashion, with a peak level 2 hrs after irradiation with 5 Gy. However, the maximal level of p53 protein in NBS cells was constantly lower than in normal cells. Moreover, this attenuation of p53 induction was confirmed by decreased levels of p21WAF1 protein, which is transcriptionally regulated by p53 protein. This defective induction of p53 protein in NBS is similar to that in ataxia-telangiectasia (AT), although the induced levels of p53 protein in NBS appeared to be the intermediate between normal cells and AT cells. This moderate p53 induction in NBS cells is consistent with the relatively mild radiation sensitivity and the abnormal cell cycle regulation post-irradiation, as present in NBS. Furthermore, all NBS cell lines used here exhibited time courses of p53 induction similar to normal cells, which is in contrast with p53 induction in AT cells, where the maximum induction shows a delay of approximately 2 hrs compared with normal cells. These evidences suggest a different function of each gene product in an upstream p53 response to radiation-induced DNA damage.
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PMID:Radiation induction of p53 in cells from Nijmegen breakage syndrome is defective but not similar to ataxia-telangiectasia. 946 63

Nijmegen breakage syndrome (NBS), which in the past also has been classified as a variant of ataxia telangiectasia (AT), is characterized by cancer proneness and extreme sensitivity to ionizing radiation. We investigated the DNA damage responses of four independent primary NBS fibroblast cell lines. Following a low dose of ionizing radiation, p53 is mostly induced with slower kinetics and shows more transient induction in NBS fibroblasts. Nonetheless, this damage-induced protein appears biologically functional: unsynchronized and synchronized NBS cells show a G1 arrest after ionizing radiation as determined by bivariate flow cytometry. Neither an AT cell line nor a NBS cell line transformed with human papillomavirus genes E6 and E7 shows a G1 arrest. Furthermore, NBS cells show a normal G2 block, unlike that shown for AT cells. These data provide a cellular distinction between NBS and AT, thereby clearly separating the NBS from the AT syndrome.
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PMID:Characterization of cell cycle checkpoint responses after ionizing radiation in Nijmegen breakage syndrome cells. 962 65

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, combined immunodeficiency, and a high incidence of lymphoid tumor. Cells from NBS patients show chromosomal instability, hypersensitivity to ionizing radiation and abnormal p53-mediated cell cycle regulation. We cloned the underlying gene for NBS, designated NBS1, by complementation-assisted positional cloning from the candidate region 8q21. Large genomic sequencing, as well as a search using computer programs, provides a powerful approach for identifying the underlying gene for a disease. The NBS1 gene encodes a protein of 754 amino acids that has FHA and BRCT domains which often are conserved in cell-cycle checkpoint proteins. The gene has weak homology to the yeast (Saccharomyces cerevisiae) Xrs2 protein in the N-terminus region. Like yeast Xrs2, the NBS1 protein forms a complex with hRAD50/hMRE11, and the complex is condensed as foci in the nucleus after irradiation, indicative that this triple-complex is a crucial factor in DNA repair. Functional analysis of the NBS1 protein is in progress and it should provide further clues to understanding the repair mechanism of radiation-induced DNA double-strand breaks.
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PMID:Positional cloning and functional analysis of the gene responsible for Nijmegen breakage syndrome, NBS1. 1083 6

p53 binding protein 1 (53BP1), a protein proposed to function as a transcriptional coactivator of the p53 tumor suppressor, has BRCT domains with high homology to the Saccharomyces cerevisiae Rad9p DNA damage checkpoint protein. To examine whether 53BP1 has a role in the cellular response to DNA damage, we probed its intracellular localization by immunofluorescence. In untreated primary cells and U2OS osteosarcoma cells, 53BP1 exhibited diffuse nuclear staining; whereas, within 5-15 min after exposure to ionizing radiation (IR), 53BP1 localized at discreet nuclear foci. We propose that these foci represent sites of processing of DNA double-strand breaks (DSBs), because they were induced by IR and chemicals that cause DSBs, but not by ultraviolet light; their peak number approximated the number of DSBs induced by IR and decreased over time with kinetics that parallel the rate of DNA repair; and they colocalized with IR-induced Mre11/NBS and gamma-H2AX foci, which have been previously shown to localize at sites of DSBs. Formation of 53BP1 foci after irradiation was not dependent on ataxia-telangiectasia mutated (ATM), Nijmegen breakage syndrome (NBS1), or wild-type p53. Thus, the fast kinetics of 53BP1 focus formation after irradiation and the lack of dependency on ATM and NBS1 suggest that 53BP1 functions early in the cellular response to DNA DSBs.
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PMID:p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. 1113 68

The checkpoint kinase Chk2 has a key role in delaying cell cycle progression in response to DNA damage. Upon activation by low-dose ionizing radiation (IR), which occurs in an ataxia telangiectasia mutated (ATM)-dependent manner, Chk2 can phosphorylate the mitosis-inducing phosphatase Cdc25C on an inhibitory site, blocking entry into mitosis, and p53 on a regulatory site, causing G(1) arrest. Here we show that the ATM-dependent activation of Chk2 by gamma- radiation requires Nbs1, the gene product involved in the Nijmegen breakage syndrome (NBS), a disorder that shares with AT a variety of phenotypic defects including chromosome fragility, radiosensitivity, and radioresistant DNA synthesis. Thus, whereas in normal cells Chk2 undergoes a time-dependent increased phosphorylation and induction of catalytic activity against Cdc25C, in NBS cells null for Nbs1 protein, Chk2 phosphorylation and activation are both defective. Importantly, these defects in NBS cells can be complemented by reintroduction of wild-type Nbs1, but neither by a carboxy-terminal deletion mutant of Nbs1 at amino acid 590, unable to form a complex with and to transport Mre11 and Rad50 in the nucleus, nor by an Nbs1 mutated at Ser343 (S343A), the ATM phosphorylation site. Chk2 nuclear expression is unaffected in NBS cells, hence excluding a mislocalization as the cause of failed Chk2 activation in Nbs1-null cells. Interestingly, the impaired Chk2 function in NBS cells correlates with the inability, unlike normal cells, to stop entry into mitosis immediately after irradiation, a checkpoint abnormality that can be corrected by introduction of the wild-type but not the S343A mutant form of Nbs1. Altogether, these findings underscore the crucial role of a functional Nbs1 complex in Chk2 activation and suggest that checkpoint defects in NBS cells may result from the inability to activate Chk2.
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PMID:Chk2 activation dependence on Nbs1 after DNA damage. 1143 75

Cell lines from Nijmegen Breakage Syndrome (NBS) and ataxia telangiectasia (A-T) patients show defective S phase checkpoint arrest. In contrast, only A-T but not NBS cells are significantly defective in radiation-induced G1/S arrest. Phosphorylation of some ATM substrates has been shown to occur in NBS cells. It has, therefore, been concluded that Nbs1 checkpoint function is S phase specific. Here, we have compared NBS with A-T cell lines (AT-5762ins137) that express a low level of normal ATM protein to evaluate the impact of residual Nbs1 function in NBS cells. The radiation-induced cell cycle response of these NBS and 'leaky' A-T cells is almost identical; normal G2/M arrest after 2 Gy, intermediate G1/S arrest depending on the dose and an A-T-like S phase checkpoint defect. Thus, the checkpoint assays differ in their sensitivity to low ATM activity. Radiation-induced phosphorylation of the ATM-dependent substrates Chk2, RPAp34 and p53-Ser15 are similarly impaired in AT-5762ins137 and NBS cells in a dose dependent manner. In contrast, NBS cells show normal ability to activate ATM kinase following irradiation in vitro and in vivo. We propose that Nbs1 facilitates ATM-dependent phosphorylation of multiple downstream substrates, including those required for G1/S arrest.
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PMID:Nbs1 promotes ATM dependent phosphorylation events including those required for G1/S arrest. 1208 6

Synthesis of p53 and WAF1 (p21) proteins was studied in cells of patients with Nijmegen breakage syndrome (NBS) and of patients with ataxia telangiectasia (AT), as well as in normal cells with respect to their response to ionizing radiation (IR). In the NBS cells, the p53 protein was progressively accumulated with increasing radiation dose and reached the maximum 2 h after exposure to radiation at a dose of 5 Gy. The amount of p53 protein was consistently lower than that in normal cells, which was correlated with low content of the WAF1, the protein regulated by p53 at the level of transcription. Suboptimal induction of p53 observed in NBS cells was also characteristic of the AT cells, though the quantitative parameters of the protein synthesis in AT cells were intermediate relative to those in normal and NBS cells. In four NBS lines, the time schedule of p53 synthesis was similar to that observed in normal cells, whereas in AT cells, induction of p53 was significantly delayed as compared to control. In response to irradiation, the amount of p53 protein synthesized in patients with AT and NBS was significantly lower than that in normal cells. The results obtained, as well as the previously published medical and genetic evidence, suggest that the two diseases are of different origin and different genes are responsible for their development.
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PMID:[Specific features of p53 protein induction after ionizing radiation in cells of patients with Nijmegen breakage syndrome]. 1217 91

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder. Originally thought to be a variant of ataxia telangiectasia (AT), the cellular phenotype of NBS has been described as almost indistinguishable from that of AT. Since the gene involved in NBS has been cloned and its functions studied, we sought to further characterize its cellular phenotype by examining the response of density-inhibited, confluent cultures of human diploid fibroblasts to irradiation in the G(0)/G(1) phase of the cell cycle. Both NBS and AT cells were markedly sensitive to the cytotoxic effects of radiation. NBS cells, however, were proficient in recovery from potentially lethal damage and exhibited a pronounced radiation-induced G(1)-phase arrest. Irradiated AT cells showed no potentially lethal damage and no G(1)-phase arrest. Both cell types were hypersensitive to the induction of chromosomal aberrations, whereas the distribution of aberrations in irradiated NBS cells was similar to that of normal controls, AT cells showed a high frequency of chromatid-type aberrations. TP53 and CDKN1A (also known as p21(Waf1)) expression was attenuated in irradiated NBS cells, but maximal induction occurred 2 h postirradiation, as was observed in normal controls. The similarities and differences in cellular phenotype between irradiated NBS and AT cells are discussed in terms of the functional properties of the signaling pathways downstream of AT involving the NBS1 and TP53 proteins.
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PMID:Differing responses of Nijmegen breakage syndrome and ataxia telangiectasia cells to ionizing radiation. 1217 9


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