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 ATM protein kinase regulates the DNA damage response by phosphorylating proteins involved in cell cycle checkpoints and DNA repair. We report here on the function of the predicted leucine zipper (LZ) motif, and sequences adjacent to this, in regulating ATM activity. The predicted LZ sequence was deleted from ATM, generating ATMDeltaLZ, and expressed in an ATM-negative AT cell line. ATM increased cell survival following exposure to ionizing radiation, whereas expression of ATMDeltaLZ failed to increase cell survival. ATMDeltaLZ retained in vitro kinase activity, but was unable to phosphorylate p53 in vivo. Leucine zippers mediate homo- and heterodimerization of proteins. However, the predicted LZ of ATM did not mediate the formation of ATM dimers. We examined if the predicted LZ of ATM was a dominant-negative inhibitor of ATM function in SW480 cells. Expression of amino acids 769-1436 of ATM, including the predicted LZ, sensitized SW480 cells to ionizing radiation, but did not inhibit ATM's kinase activity or its ability to phosphorylate Brca1. Further, this dominant-negative activity was not dependent on the predicted LZ domain. The central region of the ATM protein therefore contains multiple sequences which regulate cell survival following DNA damage.
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PMID:ATM's leucine-rich domain and adjacent sequences are essential for ATM to regulate the DNA damage response. 1450 13

The ATM gene, mutated in the cancer-prone and radiation-sensitive syndrome ataxia-telangiectasia (AT), could predispose to breast cancer (BC) development and adverse radiotherapy responses. Sixteen ATM variants were genotyped in 254 BC cases, 70 of whom were adverse radiotherapy responders (RS-BC), and 312 control subjects and the ATM haplotypes were constructed. Constitutive ATM protein, cell survival, and the p53 response after exposure to ionizing radiation were compared in lymphoblastoid cell lines (LCLs) established from the BC cases, AT, and normal individuals. The tightly linked intronic ATM polymorphisms IVS22-77 T>C and IVS48 + 238 C>G, in the homozygote state were associated with increased BC risk [IVS22-77 CC versus TT odds ratio (OR), 1.67; 95% confidence interval (CI), 1.00-2.81], and in the heterozygote state with clinical radioprotection (IVS22-77 CT versus TT OR, 0.45; 95% CI, 0.24-0.85). Homozygote carriers of the G5557A variant were over-represented in RS-BC cases compared with non-RS-BC cases (OR, 6.76; 95% CI, 1.19-38.43). These three single nucleotide polymorphisms were associated with the three major ATM haplotypes present in >80% of the study population. BC LCLs treated with ionizing radiation exhibited an intermediate cell survival and p53 response between that of normal and AT LCLs, with the response in the RS-BC LCLs being more compromised than in the non-RS-BC LCLs. Our study suggests a general pattern of increased BC risk associated with carrying any one of the ATM variants studied, with a significant association being observed in individuals carrying variants on both ATM alleles (OR, 1.75; 95% CI, 1.09-2.81) and that ATM variants may impact on radiation sensitivity.
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PMID:ATM haplotypes and cellular response to DNA damage: association with breast cancer risk and clinical radiosensitivity. 1469 86

It has been estimated that approximately 1% of the general population are ataxia telangiectasia (AT) mutated (ATM) heterozygotes. The ATM protein plays a central role in DNA-damage response pathways; however, the functional consequences of the presence of either heterozygous truncating or missense mutations on ATM expression and the ionising radiation (IR)-induced cellular phenotype remain to be fully determined. To investigate this relationship, the ATM mRNA and protein levels and several cellular end points were characterised in 14 AT heterozygote (AT het) lymphoblastoid cell lines, compared to normal and AT homozygote lines. The AT het cell lines displayed a wide range of IR-induced responses: despite lower average levels of ATM mRNA and protein expression compared to normal cells, 13 out of 14 were capable of phosphorylating the ATM substrates p53-ser15 and Chk2, leading to a normal cell cycle progression after irradiation. However, cell survival was lower than in the normal cell lines. The presence of a missense compared to a truncating mutation was associated with lower cell survival after exposure to 2 Gy irradiation (P=0.005), and a higher level of ATM mRNA expression (P=0.047). Our results underline the difficulty in establishing a reliable test for determining ATM heterozygosity.
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PMID:Cellular responses to ionising radiation of AT heterozygotes: differences between missense and truncating mutation carriers. 1497 Aug 66

Ataxia-telangiectasia (A-T) is caused by mutations of the ATM gene, the product of which is involved in the regulation of cellular responses to radiation damage. Ataxia usually starts in early childhood but a delayed age at onset and slower rate of neurological deterioration has been found for some patients with variant A-T. Only few patients have been documented to survive into the 4th decade. We report on a patient with an attenuated form of A-T who was diagnosed as having A-T by the age of 52 years and died by the age of 60 years. He was found to be a compound heterozygote for a double missense mutation (D2625E and A2626P) and a novel splicing mutation (496 + 5G --> A) of the ATM gene. Cytogenetic studies of the patient's lymphoblastoid cells revealed modest levels of bleomycin-induced chromosomal instability. Residual ATM protein was found at a level of 10-20% of wildtype. Low residual ATM kinase activity could be demonstrated towards p53, whereas it was poorly detectable towards nibrin. Our results corroborate the view that the clinical variability of A-T is partly determined by the mutation type and indicate that A-T can extend to late adulthood disease.
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PMID:Slow progression of ataxia-telangiectasia with double missense and in frame splice mutations. 1505 41

The ATM protein, which is mutated in the inherited disease ataxia telangiectasia (AT), is a key regulator of the cells' DNA damage response. AT cells also exhibit constitutive activation of transcriptional regulators such as p53, E2F, AP1, and NFkappaB. Inactivation of ATM may therefore alter the cells' transcriptional profile. ATM expression in HeLa cells was silenced with siRNA expressed from a plasmid based vector, generating a stable cell line, HeLaATM601. HeLaATM601 cells displayed minimal levels of ATM protein and had a 10-fold increase in sensitivity to ionizing radiation. DNA microarray analysis demonstrated that 35 genes were upregulated and five genes were downregulated in HeLaATM601 cells. Genes upregulated in the absence of ATM included interferon-response proteins, cell cycle regulators, integral membrane proteins, and adhesion and extracellular matrix proteins. Using real-time PCR, these genes were also upregulated in cells derived from AT patients. Inactivation of the ATM protein therefore has a significant impact on the transcriptional profile of the cell.
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PMID:Stable siRNA-mediated silencing of ATM alters the transcriptional profile of HeLa cells. 1509 73

ATM protein anticipates in the initiation of the DNA repair signal pathway and also mediates cell cycle arrest and repair. ATM deficiency predictably results in radiosensitivity, germ cell degeneration, chromosomal instability, immunodeficiency, and an extreme predisposition to tumors. Moreover, studies found that ATM is the upstream gene of the p53 pathway and would phosphorylate p53 directly after DNA damage, which would suppress tumorigenesis. Expression of ATM and p53 in 167 pancreatic cancer and 101 control specimens, benign lesions, and normal pancreata were detected by high-throughput tissue microarray and immunohistochemistry while seeking the role of ATM in the initiation and development of pancreatic carcinoma as well as its relationship with p53. We found that the positive rates of ATM and p53 expression in pancreatic carcinoma and its relative control specimen were 67.7% (113/167) and 82.2% (83/101) (P < 0.05) and 57.5% (96/167) and 5.0% (5/101) (P < 0.01), respectively. ATM positive staining is significantly relative to age and infiltration (P < 0.05), while the expression of p53 was significantly associated with tumor differentiation, lymph node metastasis, and nerve infiltration (P < 0.05). Expression of ATM and p53 was positively correlated. These findings suggest that expression of ATM deficiency may increase the transformative ability of pancreatic cancer cells. ATM may also cooperate with p53 in the repair of cell damage.
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PMID:Expression of ATM protein and its relationship with p53 in pancreatic carcinoma with tissue array. 1509 60

The ataxia-telangiectasia mutated (ATM) protein kinase is activated in response to ionizing radiation (IR) and activates downstream DNA-damage signaling pathways. Although the role of ATM in the cellular response to ionizing radiation has been well characterized, its role in response to other DNA-damaging agents is less well defined. We previously showed that genistein, a naturally occurring isoflavonoid, induced increased ATM protein kinase activity, ATM-dependent phosphorylation of p53 on serine 15 and activation of the DNA-binding properties of p53. Here, we show that genistein also induces phosphorylation of p53 at serines 6, 9, 20, 46, and 392, and that genistein-induced accumulation and phosphorylation of p53 is reduced in two ATM-deficient human cell lines. Also, we show that genistein induces phosphorylation of ATM on serine 1981 and phosphorylation of histone H2AX on serine 139. The related bioflavonoids, daidzein and biochanin A, did not induce either phosphorylation of p53 or ATM at these sites. Like genistein, quercetin induced phosphorylation of ATM on serine 1981, and ATM-dependent phosphorylation of histone H2AX on serine 139; however, p53 accumulation and phosphorylation on serines 6, 9, 15, 20, 46, and 392 occurred in ATM-deficient cells, indicating that ATM is not required for quercetin-induced phosphorylation of p53. Our data suggest that genistein and quercetin induce different DNA-damage induced signaling pathways that, in the case of genistein, are highly ATM-dependent but, in the case of quercetin, may be ATM-dependent only for some downstream targets.
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PMID:The isoflavonoids genistein and quercetin activate different stress signaling pathways as shown by analysis of site-specific phosphorylation of ATM, p53 and histone H2AX. 1517 39

We describe here the cloning of full-length ataxia-telangiectasia mutated (ATM) cDNA and characterization of its activity. Full-length ATM cDNA is cloned into an inducible EBV-based vector (pMEP4) and its expression analyzed in a stably transfected cell line. ATM protein induction is monitored by immunoblotting with antibodies against both ATM and a FLAG sequence tag in the recombinant protein. Extracts from irradiated cells are immunoprecipitated with anti-ATM antibodies, and protein kinase activity is measured using p53(1-44)-specific substrate or by immunoblotting extracts with an anti-phosphoserine 15 p53-specific antibody. Missense mutations affecting ATM kinase activity are detected using in vitro mutagenesis of ATM cDNA followed by the procedures outlined above.
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PMID:Analyzing the regulation and function of ATM. 1522 May 28

The ataxia-telangiectasia mutated (ATM) gene product plays a role in responding to double stand DNA breaks. Some biochemical studies of ATM function have been hampered by lack of an efficient expression system and abundant purified ATM protein. We report the construction of a vaccinia virus expressing ATM, vWR-ATM, which was used to produce large amounts of functional FLAG-tagged ATM protein (FLAG-ATM) in HeLa cells. Kinase activity of the purified FLAG-ATM was dependent on manganese and inhibited with wortmannin. Using the FLAG-ATM recombinant protein, GST-p53 serine 15 phosphorylation increased in the presence of damaged DNA. PHAS-1 phosphorylation was found to be DNA independent. Purified FLAG-ATM was recovered in the autophosphorylated form, as demonstrated by phosphorylation of ATM serine 1981. As shown by atomic force microscopy, FLAG-ATM bound to linear DNA both at broken ends and in mid-strands. Vaccinia virus is the most efficient ATM expression system described to date.
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PMID:ATM protein purified from vaccinia virus expression system: DNA binding requirements for kinase activation. 1531 75

Epidemiological studies have indicated that ataxia-telangiectasia (AT) heterozygotes in AT families have an increased risk of cancer, particularly of breast cancer (BC). However, in BC case-control studies, no significant differences were found in the frequency of ATM mutations between patients and controls. In such studies missense mutations were found more frequently than truncating mutations, suggesting that the cancer risk depends on mutation type. To investigate this possibility, we assessed the risk of BC according to the type and position of the ATM truncating mutation in extended AT families. DNA or RNA that had been isolated from blood or buccal cells of AT children and their relatives was screened for ATM germ-line mutations using restriction endonuclease fingerprinting, the protein truncation test, fluorescence-assisted mismatch analysis, and direct sequencing. The standardized incidence ratio of cancer associated with ATM heterozygosity status and type of mutation was estimated. We tested for genotype-phenotype correlations by simulations, permuting mutations among parental branches. No significant difference was found in the relative risk of breast cancer or any other type of cancer based on mutation type. However, the occurrence of BC may be associated with truncating mutations in certain binding domains of the ATM protein (e.g., P53/BRCA1, beta-adaptin, and FAT domains; P = 0.006). In this limited sample set, the presence of missense or truncating ATM mutations was not associated with different cancer risks. The risk of BC appeared to be associated with the alteration of binding domains rather than with the length of the predicted ATM protein.
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PMID:Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families. 1539 Jan 80


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