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)

In addition to conferring an indefinite replicative life span, telomerase renders p16(-) human mammary epithelial cells (HMEC) resistant to growth arrest by TGFbeta or by loss of EGF or insulin signaling. In contrast to earlier reports, we recently found that growth factor signaling was not directly affected by telomerase expression. Rather, short dysfunctional or near-dysfunctional telomeres in proliferating telomerase(-) HMEC sensitized the cells to p53-dependent signals for growth arrest. We showed that during serial passage and before any signs of replicative senescence, HMEC lacking telomerase experience enhanced p53 stability and DNA damage signaling, as determined by increased phosphorylation on p53-Ser15 and Chk2-Thr68, and formation of 53BP1/phosphorylated histone H2AX foci at chromosome ends. This heightened activity of the p53 pathway enhanced the efficiency with which cells arrested growth in response to TGFbeta or to EGF or insulin withdrawal, and was abolished by ectopic expression of hTERT, the catalytic subunit of telomerase. Telomerase elongated short telomeres, thereby reducing the basal level of activated p53 and raising cellular tolerance for other p53-dependent signals, including those emanating from non-genotoxic sources. These findings explain a number of observed effects of telomerase expression on cell growth and survival without postulating additional functions for telomerase.
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PMID:Soothing the watchman: telomerase reduces the p53-dependent cellular stress response. 1753 47

MDC1 and 53BP1 are critical components of the DNA damage response (DDR) machinery that protects genome integrity and guards against cancer, yet the tissue expression patterns and involvement of these two DDR adaptors/mediators in human tumours remain largely unknown. Here we optimized immunohistochemical analyses of human 53BP1 and MDC1 proteins in situ and identified their virtually ubiquitous expression, both in proliferating and quiescent, differentiated tissues. Focus formation by 53BP1 and/or MDC1 in human spermatogenesis and subsets of breast and lung carcinomas indicated physiological and 'pathological' activation of the DDR, respectively. Furthermore, aberrant reduction or lack of either protein in significant proportions of carcinomas supported the candidacy of 53BP1 and MDC1 for tumour suppressors. Contrary to carcinomas, almost no activation or loss of MDC1 or 53BP1 were found among testicular germ-cell tumours (TGCTs), a tumour type with unique biology and exceptionally low incidence of p53 mutations. Such concomitant presence (in carcinomas) or absence (in TGCTs) of DDR activation and DDR aberrations supports the roles of MDC1 and 53BP1 within the ATM/ATR-regulated checkpoint network which, when activated, provides an early anti-cancer barrier the pressure of which selects for DDR defects such as p53 mutations or loss of 53BP1/MDC1 during cancer progression.
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PMID:DNA damage response mediators MDC1 and 53BP1: constitutive activation and aberrant loss in breast and lung cancer, but not in testicular germ cell tumours. 1754 51

p53-Binding protein 1 (53BP1) encodes a critical checkpoint protein that localizes to sites of DNA double-strand breaks (DSBs) and participates in DSB repair. Mice that are 53bp1 deficient or hemizygous have an increased incidence of lymphoid malignancies. However, 53BP1 abnormalities in primary human tumors have not been described. By combining high-density single nucleotide polymorphism (HD SNP) array data and gene expression profiles, we found 9 of 63 newly diagnosed human diffuse large B-cell lymphomas (DLBCLs) with single copy loss of the chromosome 15q15 region including the 53BP1 locus; these nine tumors also had significantly lower levels of 53BP1 transcripts. 53BP1 single copy loss found with the HD SNP array platform was subsequently confirmed by fluorescence in situ hybridization. These studies highlight the role of 53BP1 copy loss in primary human DLBCLs and the value of integrative analyses in detecting this genetic lesion in human tumors.
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PMID:Integrative analysis reveals 53BP1 copy loss and decreased expression in a subset of human diffuse large B-cell lymphomas. 1763 49

Loss of the control over cellular proliferation can lead to cell death or result in the abnormal proliferation characteristic of the cancerous state. Among the controls used to achieve normal cellular proliferation is the DNA damage checkpoint pathway that monitors genome integrity (Hartwell and Kastan 1994). 53BP1 was identified as a protein that interacts with the DNA-binding core domain of the tumor suppressor p53. The p53-binding region of 53BP1 maps to the C-terminal BRCT domains which are homologous to those found in the breast cancer protein BRCA1 and in other proteins involved in the DNA damage response, notably budding yeast Rad9. In addition to its recently reported role in sensing double strand breaks, 53BP1 is believed to have roles, currently ill understood, in many aspects of DNA metabolism ranging from transcription and class switch recombination to 'mediating' the DNA damage checkpoint response (Chai et al. 1999; Huyen et al. 2004; Sengupta et al. 2004; Ward et al. 2004). Here, we investigate 53BP1 complex formation. We investigate 53BP1 oligomerization and show that this is not dependent on the presence of disulfide bridges.
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PMID:An investigation into 53BP1 complex formation. 1769 20

p53, the tumour suppressor and transcriptional activator, is regulated by numerous post-translational modifications, including lysine methylation. Histone lysine methylation has recently been shown to be reversible; however, it is not known whether non-histone proteins are substrates for demethylation. Here we show that, in human cells, the histone lysine-specific demethylase LSD1 (refs 3, 4) interacts with p53 to repress p53-mediated transcriptional activation and to inhibit the role of p53 in promoting apoptosis. We find that, in vitro, LSD1 removes both monomethylation (K370me1) and dimethylation (K370me2) at K370, a previously identified Smyd2-dependent monomethylation site. However, in vivo, LSD1 shows a strong preference to reverse K370me2, which is performed by a distinct, but unknown, methyltransferase. Our results indicate that K370me2 has a different role in regulating p53 from that of K370me1: K370me1 represses p53 function, whereas K370me2 promotes association with the coactivator 53BP1 (p53-binding protein 1) through tandem Tudor domains in 53BP1. Further, LSD1 represses p53 function through the inhibition of interaction of p53 with 53BP1. These observations show that p53 is dynamically regulated by lysine methylation and demethylation and that the methylation status at a single lysine residue confers distinct regulatory output. Lysine methylation therefore provides similar regulatory complexity for non-histone proteins and for histones.
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PMID:p53 is regulated by the lysine demethylase LSD1. 1780 99

The epidemiological association between cancer and exposure to ambient air pollution particles (particles with a 50% cut-off aerodynamic diameter of 10 microm (PM(10))) has been related to the ability of PM(10) and its constituent nanoparticles (NPs) to cause reactive oxidative species (ROS)-driven DNA damage. However, there are no data on the molecular response to these genotoxic effects. In order to assess whether PM(10), NP and ROS-driven DNA damage induce carcinogenesis pathways, A549 cells were treated with tert-butyl-hyperperoxide (Tbh), urban dust (UD), carbon black (CB), nanoparticulate CB (NPCB), benzo(a)pyrene (BaP) and NPCB coated with BaP for <or=24 h. Single- and double-strand breakage of DNA was determined by comet assay; cell cycle status was analysed using flow cytometry. Nuclear extracts or acid-extracted histones were used for Western blot analysis of p-ser15-p53 (p53 phosphorylated at ser15), p53 binding protein (53BP) 1, phospho-histone H2A.X (p-H2A.X) and phospho-BRCA1 (p-BRCA1). UD caused both single- and double-strand DNA breaks, while other tested NPs caused only single-strand DNA breaks. NPs significantly altered cell cycle kinetics. Tbh enhanced p-H2A.X after 1 and 6 h (2.1- and 2.2-fold, respectively). NP increased 53BP1 expression at 1 h (2.4-8.7-fold) and p-BRCA1 at 1-6 h. N-acetylcysteine blocked NP-driven p-ser15-p53 response. In conclusion, nanoparticles and reactive oxidative species induce DNA damage, activating p53 and proteins related to DNA repair, mimicking irradiation-related carcinogenesis pathways.
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PMID:Nanoparticle-driven DNA damage mimics irradiation-related carcinogenesis pathways. 1805 54

Several DNA damage checkpoint factors form nuclear foci in response to ionizing radiation (IR). Although the number of the initial foci decreases concomitantly with DNA double-strand break repair, some fraction of foci persists. To date, the physiological role of the persistent foci has been poorly understood. Here we examined foci of Ser1981-phosphorylated ATM in normal human diploid cells exposed to 1Gy of X-rays. While the initial foci size was approximately 0.6microm, the one or two of persistent focus (foci) grew, whose diameter reached 1.6microm or more in diameter at 24h after IR. All of the grown persistent foci of phosphorylated ATM colocalized with the persistent foci of Ser139-phosphorylated histone H2AX, MDC1, 53BP1, and NBS1, which also grew similarly. When G0-synchronized normal human cells were released immediately after 1Gy of X-rays and incubated for 24h, the grown large phosphorylated ATM foci (> or =1.6microm) were rarely (av. 0.9%) observed in S phase cells, while smaller foci (<1.6microm) were frequently (av. 45.9%) found. We observed significant phosphorylation of p53 at Ser15 in cells with a single grown phosphorylated ATM focus. Furthermore, persistent inhibition of foci growth of phosphorylated ATM by an ATM inhibitor, KU55933, completely abrogated p53 phosphorylation. Defective growth of the persistent IR-induced foci was observed in primary fibroblasts derived from ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) patients, which were abnormal in IR-induced G1 checkpoint. These results indicate that the growth of the persistent foci of the DNA damage checkpoint factors plays a pivotal role in G1 arrest, which amplifies G1 checkpoint signals sufficiently for phosphorylating p53 in cells with a limited number of remaining foci.
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PMID:Growth of persistent foci of DNA damage checkpoint factors is essential for amplification of G1 checkpoint signaling. 1824 56

Mutations in NBS1 gene are related to higher occurrence of malignancies. In this work we studied response of T-lymphocyte leukemia cells MOLT-4 to ionizing radiation. We detected IRIF (ionizing radiation forming foci) containing histone gammaH2A.X, protein 53BP1, and Nbs1, which were formed around double-strand breaks of DNA. We found dose-dependent increase in foci number (colocalization of gammaH2A.X and 53BP1) and gammaH2A.X amount (integral optical density) 1h after irradiation. After the dose of 1.5 Gy the number of foci decreases with time, but 72 h after irradiation 9% of live cells still contained big foci around unrepaired DNA damage. Western blot method revealed massive phosphorylation of H2A.X during apoptosis induction, 6-24 h after irradiation by the doses 1.5 and 3 Gy. Cells with apoptotic morphology showed strong phosphorylation of H2A.X, but it was not accompanied by 53BP1. 1h after irradiation by the lethal doses 5 and 10 Gy we detected by Western blot a decrease in repair proteins Mre11, Rad50, and Nbs1. While phosphorylation of H2A.X 1h after irradiation was detected by both confocal microscopy and Western blot, phosphorylation of Nbs1 on serine 343 was not detectable in MOLT-4 cells. Despite functional ATM and p53 the phosphorylation of Nbs1 on serine 343 was impaired in these cells, and might be responsible for high radiosensitivity of MOLT-4 cells.
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PMID:Is defect in phosphorylation of Nbs1 responsible for high radiosensitivity of T-lymphocyte leukemia cells MOLT-4? 1826 46

Epidermal cells are the first cells to be exposed to environmental genotoxic agents such as ultraviolet and ionizing radiations, which induce DNA double strand breaks (DSB) and activate DNA damage response (DDR) to maintain genomic integrity. Defective DDR can result in genomic instability (GIN) which is considered to be a central aspect of any carcinogenic process. P53-binding protein 1 (53BP1) belongs to a family of evolutionarily conserved DDR proteins. Because 53BP1 molecules localize at the sites of DSB and rapidly form nuclear foci, the presence of 53BP1 nuclear foci can be considered as a cytological marker for endogenous DSB reflecting GIN. The levels of GIN were analyzed by immunofluorescence studies of 53BP1 in 56 skin tumors that included 20 seborrheic keratosis, eight actinic keratosis, nine Bowen's disease, nine squamous cell carcinoma, and 10 basal cell carcinoma. This study demonstrated a number of nuclear 53BP1 foci in human skin tumorigenesis, suggesting a constitutive activation of DDR in skin cancer cells. Because actinic keratosis showed a high DDR type of 53BP1 immunoreactivity, GIN seems to be induced at the precancerous stage. Furthermore, invasive cancers exhibited a high level of intense, abnormal 53BP1 nuclear staining with nuclear accumulation of p53, suggesting a disruption of DDR leading to a high level of GIN in cancer cells. The results of this study suggest that GIN has a crucial role in the progression of skin carcinogenesis. The detection of 53BP1 expression by immunofluorescence can be a useful histological marker to estimate the malignant potential of human skin tumors.
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PMID:Alteration of p53-binding protein 1 expression during skin carcinogenesis: association with genomic instability. 1838 Jul 89

The cellular DNA damage response (DDR) entails the activation of ATM, ATR and/or DNA PK protein kinases that causes modifications of proteins including Chk1, Chk2 and 53BP1, aggregation of DDR proteins into foci, and activation of p53. The DDR is thought to be required for initiation and maintenance of cellular senescence. Potentially senescent cells with DNA damage foci occur in large numbers in vivo with many diseases, but, with the exception of mammalian dermis, there is little evidence for that with normal aging. After experimental induction of cellular senescence in the livers of juvenile mice, there was robust expression of DDR markers in hepatocytes at 1 week; however, by 7 weeks, activation of ATM/ATR kinase targets was limited, although cells with DNA damage foci were present. An analysis of hepatocytes of aged, 22-month-old mice, not experimentally exposed to genotoxins, showed limited activation of ATM/ATR targets, though high numbers of cells with DNA damage foci were found, similar to that seen many weeks after artificial senescence induction in young mice. Based on senescence heterochromatin and SA ss Gal assays of the 22-month-old mouse liver, more than 20% of hepatocytes were potentially senescent, though only some components of the DDR were enriched.
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PMID:Modification of the ATM/ATR directed DNA damage response state with aging and long after hepatocyte senescence induction in vivo. 1844 May 96


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