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)

Sporadic breast carcinoma is associated with multiple genetic alterations. The clinical relevance of these alterations, however, needs further clarification. In the present study we analyzed 266 spontaneously arising breast carcinomas for allelic losses in the BRCA1 and TP53 regions on chromosome 17, the BRCA2 region on chromosome 13, the ATM (mutated in ataxia-telangiectasia) region on chromosome 11 and on the chromosomal arms 7q and 16q. In addition the following clinical and pathological parameters were evaluated: age at diagnosis, tumor size, presence or absence of regional and distant metastases, hormone-receptor status, histopathological classification and tumor grading. The analysis of genetic and clinical observations revealed significant associations: absence of expression of the estrogen receptor was linked to a high rate of allelic losses of markers in the BRCA1, TP53 and BRCA2 regions. Expression of the progesterone receptor coincided with allelic loss on the long arm of chromosome 16. High-grade malignant lesions and ductal differentiation were frequently associated with allelic losses in the proximal portion of chromosome 17q. The accumulation of multiple allelic deletions was linked to high-grade malignant tumors, to tumor size, and to loss of expression of the estrogen receptor. Our data point to a relationship between clinically relevant prognostic factors and specific genomic deletions in the BRCA1, BRCA2 and TP53 region.
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PMID:Genomic deletions in the BRCA1, BRCA2 and TP53 regions associate with low expression of the estrogen receptor in sporadic breast carcinoma. 922 12

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

Ataxia-telangiectasia (A-T) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients and has long been associated with chromosomal instability. By analysing tumour DNA from patients with sporadic T-cell prolymphocytic leukaemia (T-PLL), a rare clonal malignancy with similarities to a mature T-cell leukaemia seen in A-T, we demonstrate a high frequency of ATM mutations in T-PLL. In marked contrast to the ATM mutation pattern in A-T, the most frequent nucleotide changes in this leukaemia were missense mutations. These clustered in the region corresponding to the kinase domain, which is highly conserved in ATM-related proteins in mouse, yeast and Drosophila. The resulting amino-acid substitutions are predicted to interfere with ATP binding or substrate recognition. Two of seventeen mutated T-PLL samples had a previously reported A-T allele. In contrast, no mutations were detected in the p53 gene, suggesting that this tumour suppressor is not frequently altered in this leukaemia. Occasional missense mutations in ATM were also found in tumour DNA from patients with B-cell non-Hodgkin's lymphomas (B-NHL) and a B-NHL cell line. The evidence of a significant proportion of loss-of-function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T-PLL and suggests that ATM acts as a tumour suppressor. As constitutional DNA was not available, a putative hereditary predisposition to T-PLL will require further investigation.
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PMID:Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. 928 6

Checkpoint controls arrest cells with defects in DNA replication or DNA damage. For several reasons, checkpoint controls may be relevant to ontogeny and treatment of cancer. Firstly, mutations in two human genes, TP53 and ATM, give rise to cellular defects in cell cycle checkpoints and are associated with cancer. Secondly, although checkpoint defects potentially render the cell damage sensitive, they may do so only in combination with other defects in the cell's response to damage. Therefore, manipulation of checkpoint defects, requiring a description of normal and mutant pathways, will be required for this type of therapeutic approach. Those pathways are being described in yeast cells. In budding yeast, the study of checkpoint genes has led to the view that these genes have many roles in the cellular responses to DNA damage, including roles in arrest in multiple stages of cell cycle, in transcriptional induction of repair genes, in DNA repair itself and additionally some undefined role in DNA replication. The checkpoint pathways and proteins that carry out these responses may consist of sensor proteins that detect damage, signaller proteins that transduce an inhibitory signal and target proteins that are altered to arrest cell division (or cause other changes in cell behaviour). Yeast genes that may act at each step have been identified, leading to a working model of checkpoint pathways. An initial step in the pathway may involve the processing of damage to an intermediate that signals arrest and acts in DNA repair. Human checkpoint pathways may have defects in processing damage as well.
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PMID:Yeast checkpoint controls and relevance to cancer. 933 99

The autosomal recessive disorder ataxia-telangiectasia (AT) is highly pleiotropic. It is characterized by gradual loss of Purkinje cells in the cerebellum, leading to progressive neuromotor deterioration, immunodeficiency, developmental defects in specific tissues, profound predisposition to malignancy and acute sensitivity to ionizing radiation. AT cells show chromosomal instability, premature senesence, radiosensitivity and defects in cell cycle checkpoints activated by ionizing radiation. Several radiation induced pathways that regulate the cell cycle seem to be defective in AT cells, at least one of which is mediated by TP53. Extensive characterization of the cellular defects of AT cells, together with the recent isolation of the ATM gene, has provided some insight into the possible physiological roles of the ATM protein. Several lines of evidence, including the nature of the agents that elicit the hypersensitivity of AT cells, point to the possibility of a defect in the response to damage induced by oxidative stress, which affects various cellular macromolecules. The ATM protein might have a role in activating defence mechanisms against oxidative stress. This hypothesis broadens the previous concept of the AT defect and explains several aspects of the AT phenotype that cannot be accounted for by defective processing of DNA damage.
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PMID:The ATM gene and protein: possible roles in genome surveillance, checkpoint controls and cellular defence against oxidative stress. 933 5

Certain growth regulatory kinases contain a common domain related to the phospho-inositol 3 (PI-3) kinase catalytic site. These include the ATM gene product, DNA-PKcs, and the target of rapamycin (TOR in yeast; and FRAP in mammalian cells). Rapamycin inhibits growth factor signalling and induces G1 arrest in many cell types. Some growth regulatory PI-3 kinases appear functionally linked to p53 and we have explored potential links between cellular effects induced by rapamycin and p53. In p53 null cells rapamycin inhibited cell cycling but did not induce G1 arrest. In cells which showed selective G1 arrest in response to rapamycin, rapamycin had no effect on basal levels of p53 protein. Similarly p21(WAF1) protein was not induced by rapamycin. The kinetics of the cellular p53/p21(WAF1) response to ionising radiation was unaffected by rapamycin; and the ability of growth factor to protect against p53-mediated apoptosis in response to DNA damage was also unaffected by rapamycin. The ATM gene is mutated in the cancer susceptibility syndrome ataxia telangiectasia (AT) but such mutant cells showed a similar sensitivity to rapamycin compared to their normal counterparts. RKO cell lines of common genetic background, but with different levels of functional p53 protein, also responded similarly to rapamycin. Thus, although rapamycin and p53 are each able to induce G1 arrest, they appear to act through independent growth regulatory pathways.
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PMID:Rapamycin and p53 act on different pathways to induce G1 arrest in mammalian cells. 934 96

Data are presented demonstrating that DNA damage leads to specific post-translational modifications of p53 protein. Using two-dimensional peptide mapping of in vivo radiolabeled p53 tryptic phosphopeptides, recombinant truncated p53 protein, and synthetic p53 tryptic peptides, a unique p53 phosphopeptide was identified after exposure of ML-1 cells to ionizing irradiation. This peptide represents the first 24 amino acids of p53 and contains three phosphorylated serine residues. A specific p53 phosphopeptide antibody identified serine-15 as one of the two serines in p53 that becomes phosphorylated following DNA damage induced by either ionizing irradiation (IR) or ultraviolet (UV) irradiation in multiple cell types. IR-induced phosphorylation of p53 does not affect the kinetics of p53 binding to or dissociating from DNA as assessed by electrophoretic mobility-shift assays. However, p53 phosphorylation induced by DNA damage correlates with enhanced transcription of downstream p53 target genes. Low levels of phosphoserine-15 p53 are detectable within 6 hr after IR in AT cells, whereas lymphoblasts from normal individuals exhibit this modification within 1 hr. In contrast, phosphorylation of p53 on serine-15 is similar in normal and AT cells after UV irradiation. Our results indicate that p53 is phosphorylated in response to DNA damage, that this de novo phosphorylation may be involved in the subsequent induction and activation of p53, and that although ATM affects the kinetics of p53 phosphorylation after IR, it is not absolutely required for phosphorylation of p53 on serine-15.
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PMID:DNA damage induces phosphorylation of the amino terminus of p53. 940 38

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

Somatic cells undergo a limited number of doublings in culture and enter an irreversible block in the G1 and G2/M phase of the cell cycle termed "senescence". Telomere shortening presumably as a consequence of the end-replication problem has been proposed to act as a mitotic clock eventually leading to cellular senescence. Several models have been proposed to explain how telomere shortening can lead to cellular senescence. We proposed previously that telomere shortening may eventually lead to formation of dicentric chromosomes which on subsequent breakage activate a DNA damage response pathway involving the p53 protein. Hence we proposed that the telomere shortening signal is perceived by the cell as DNA damage. Recently we have obtained experimental evidence that the p53 protein is activated posttranslationally in human fibroblasts which undergo telomere shortening and subsequent senescence in culture. In this paper we also show that the increased activity of p53 protein coincides with formation of dicentric chromosomes and senescence. Also, we have previously found that an increase in the level of the down stream target of p53 protein, p21WAF1/SD11/C1P1, is dependent on both p53 and p300 proteins. We have also shown that fibroblasts obtained from individuals with Ataxia Telangiectasia lose telomeric DNA at an accelerated rate, activate p53 protein, and undergo premature senescence in culture. These results suggest that the ataxia-telangiectasia gene (ATM) and p53 are involved in surveillance and regulation of telomeric DNA. Once a critical length of telomeric DNA is reached. ATM and p53 sense and relay this signal to the cell cycle leading to senescence.
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PMID:Critical telomere shortening regulated by the ataxia-telangiectasia gene acts as a DNA damage signal leading to activation of p53 protein and limited life-span of human diploid fibroblasts. A review. 946 55

We investigated the requirements for protein p53 and the ATM gene product in radiation-induced inhibition of DNA synthesis and regulation of the cyclin E/ and cyclin A/cyclin dependent kinases (Cdks). Wild type (WT) mouse lung fibroblasts (MLFs), p53(-/-) knock-out MLFs, normal human skin fibroblasts (HSF-55), and human AT skin fibroblasts (GM02052) were used in the investigations. The absence of p53 had no significant effect on the inhibition or recovery of DNA synthesis throughout the S phase, as determined from BrdU labeling and flow cytometry, or the rapid inhibition of cyclin A/Cdks. Gamma radiation (8 Gy) inhibited DNA synthesis and progression into G2 during the first 3 h after irradiation, and the recovery of these processes occurred at similar rates in both WT and p53(-/-) MLFs. The cyclin A/Cdks were inhibited 55-70% at 1 h after irradiation in both cell types, but p21WAF1/Cip1 levels or p21 interaction with Cdk2 did not increase in the irradiated p53(-/-) MLFs. Although p53(-/-) MLFs do not exhibit prolonged arrest at a G1 checkpoint, radiation did induce a rapid 20% reduction and small super-recovery of cyclin E/Cdk2 within 1-2 h after irradiation. Similar inhibition and recovery of cyclin E/Cdk2 previously had been associated with regulation of transient G1 delay and the inhibition of initiation at an apparent G1/S checkpoint in Chinese hamster cells. In contrast, loss of the ATM gene product abrogated transient cyclin E/Cdk2 inhibition, most inhibition of DNA synthesis and all, but a 10-15% inhibition, of the cyclin A/Cdks. The results indicate that neither p53 nor p21 is required for transient inhibition of cyclin E/Cdk2 associated with the G1/S checkpoint or for inhibition of DNA synthesis at 'checkpoints' within the S phase. Conversely, the ATM gene product appears to be essential for regulation of the G1/S checkpoint and for inhibition of DNA replication associated with the inhibition of cyclin A/Cdk2. Differential aspects of DNA synthesis inhibition among cell types are presented and discussed in the context of S phase checkpoints.
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PMID:Requirements for p53 and the ATM gene product in the regulation of G1/S and S phase checkpoints. 948 36


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