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)

Homologous recombination is a double-strand break repair pathway required for resistance to DNA damage and maintaining genomic integrity. In mitotically dividing vertebrate cells, the primary proteins involved in homologous recombination repair are RAD51 and the five RAD51 paralogs, RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3. In the absence of Rad51d, human and mouse cells fail to proliferate, and mice defective for Rad51d die before birth, likely as a result of genomic instability and p53 activation. Here, we report that a p53 deletion is sufficient to extend the life span of Rad51d-deficient embryos by up to 6 days and rescue the cell lethal phenotype. The Rad51d-/- Trp53-/- mouse embryo-derived fibroblasts were sensitive to DNA-damaging agents, particularly interstrand cross-links, and exhibited extensive chromosome instability including aneuploidy, chromosome fragments, deletions, and complex rearrangements. Additionally, loss of Rad51d resulted in increased centrosome fragmentation and reduced levels of radiation-induced RAD51-focus formation. Spontaneous frequencies of sister chromatid exchange were not affected by the absence of Rad51d, but sister chromatid exchange frequencies did fail to be induced upon challenge with the DNA cross-linking agent mitomycin C. These findings support a crucial role for mammalian RAD51D in normal development, recombination, and maintaining mammalian genome stability.
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PMID:Extensive chromosomal instability in Rad51d-deficient mouse cells. 1578 18

Increased cell killing after exposure to low acute doses of X rays (0-0.5 Gy) has been demonstrated in cells of a number of human tumor cell lines. The mechanisms underlying this effect have been assumed to be related to a threshold dose above which DNA repair efficiency or fidelity increases. We have used cells of two radioresistant human tumor cell lines, one that shows increased sensitivity to low radiation doses (T98G) and one that does not (U373), to investigate the DNA damage response at low doses in detail and to establish whether there is a discontinuous dose response or threshold in activation of any important mediators of this response. In the two cell lines studied, we found a sensitive, linear dose response in early signaling and transduction pathways between doses of 0.1 and 2 Gy with no evidence of a threshold dose. We demonstrate that ATM-dependent signaling events to downstream targets including TP53, CHK1 and CHK2 occur after doses as low as 0.2 Gy and that these events promote an effective damage response. Using chemical inhibition of specific DNA repair enzymes, we show that inhibition of DNA-PK-dependent end joining has relatively little effect at low (<1 Gy) doses in hyper-radiosensitive cells and that at these doses the influence of RAD51-mediated repair events may increase, based on high levels of RAD51/BRCA2 repair foci. These data do not support a threshold model for activation of DNA repair in hyper-radiosensitive cells but do suggest that the balance of repair enzyme activity may change at low doses.
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PMID:DNA damage responses at low radiation doses. 1613 2

In response to DNA breaks, human cells delay their progression through the G1, S, and G2 phases of the cell cycle. This response requires the coordinated effort of the ATM-CHK2-p53 and ATR-CHK1 DNA damage-sensing pathways and DNA repair (eg, DNA-PK and RAD51 complexes). The turnover of many of these DNA damage-associated proteins is controlled by the 26S proteasome. In this article, we review molecular strategies that target each of these pathways using silencing RNA (siRNA), antisense, or small-molecule inhibition. Although these agents can radiosensitize tumor cells, little data are available regarding potential effects on normal tissues to determine the potential therapeutic ratio of these strategies after fractionated radiotherapy. Clinical trials using such agents will require novel correlative science endpoints to track DNA repair and cell-cycle arrest and will need careful assessment of normal tissue toxicity and stability.
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PMID:Radiation and new molecular agents part I: targeting ATM-ATR checkpoints, DNA repair, and the proteasome. 1637 7

Breast cancer is the most common cancer in women and a significant cause of death. Mutations of the oncosuppressor genes BRCA1 and BRCA2 are associated with a hereditary risk of breast cancer, and dysregulation of their expression has been observed in sporadic cases. Soya isoflavones have been shown to inhibit breast cancer in studies in vitro, but associations between the consumption of isoflavone-containing foods and breast cancer risk have varied in epidemiological studies. Soya is a unique source of the phytoestrogens daidzein (4',7-dihydroxyisoflavone) and genistein (4',5,7-trihydroxyisoflavone), two molecules that are able to inhibit the proliferation of human breast cancer cells in vitro. The aim of the present study was to determine the effects of genistein (5 microg/ml) and daidzein (20 microg/ml) on transcription in three human breast cell lines (one dystrophic, MCF10a, and two malignant, MCF-7 and MDA-MB-231) after 72 h treatment. The different genes involved in the BRCA1 and BRCA2 pathways (GADD45A, BARD1, JUN, BAX, RB1, ERalpha, ERbeta, BAP1, TNFalpha, p53, p21Waf1/Cip1, p300, RAD51, pS2, Ki-67) were quantified by real-time quantitative RT-PCR, using the TaqMan method and an ABI Prism 7700 Sequence Detector (Applied Biosystems). We observed that, in response to treatment, many of these genes were overexpressed in the breast cancer cell lines (MCF-7 and MDA-MB-231) but not in the dystrophic cell line (MCF10a).
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PMID:Soya phytonutrients act on a panel of genes implicated with BRCA1 and BRCA2 oncosuppressors in human breast cell lines. 1646 60

We have investigated p53-related differences in cellular response to DNA damaging agents, focusing on p53s effects on RAD51 protein level and sub-cellular localization post exposure to ionizing radiation. In a human colon cancer cell line, HCT116 and its isogenic p53-/- subcell line we show here p53-independent RAD51 foci formation but interestingly the resolution of RAD51 foci showed clear p53 dependence. In p53 wt cells, but not in p53-/- cells, RAD51 protein level decreased 48 h post irradiation and fluorescence immunostaining showed resolution of RAD51 foci and relocalization of RAD51 to nucleoli at time points corresponding to the decrease in RAD51 protein level. Both cell lines rejoined DNA double strand breaks efficiently with similar kinetics and p53 status did not influence sensitivity to DNA damaging agents. We suggest that p53 has a role in RAD51 clearance post DSB repair and that nucleoli might be sites of RAD51 protein degradation.
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PMID:p53 is involved in clearance of ionizing radiation-induced RAD51 foci in a human colon cancer cell line. 1651 53

Radiation therapy and chemotherapy are commonly used treatments for head and neck cancer. RAD51 is a highly conserved DNA repair protein that serves a central function in the homologous recombination pathway. High levels of RAD51 protein expression have been reported in number of human cancer cell lines, and studies suggest that RAD51 overexpression can increase cellular resistance to radiation and some chemotherapeutic drugs. In this study, RAD51 protein levels were quantified by immunohistochemistry in tumor samples from twelve head and neck cancer patients who received identical treatment with induction chemotherapy (paclitaxel and carboplatinum) followed by radiation therapy given concurrently with additional chemotherapy (paclitaxel, fluorouracil, hydroxyurea). Patients with high RAD51 protein levels in their pre-treatment tumor biopsies demonstrated poorer cancer-specific survival rates than patients with lower RAD51 levels (33.3% vs. 88.9% at 2 years; p=0.025). In addition, within a subgroup of patients with normal tumor cell p53 expression, there was a non-significant trend toward better induction chemotherapy response rates observed in the tumors with lower RAD51 protein levels. These results suggest that tumor cell RAD51 expression levels may influence the outcome of patients with head and neck cancer treated with chemotherapy and radiotherapy.
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PMID:Pilot study examining tumor expression of RAD51 and clinical outcomes in human head cancers. 1659 27

RAD51 participates in homologous recombination (HR) repair of double-stranded DNA breaks (DSBs) that may cause genomic instability and cancer. Two single-nucleotide polymorphisms (SNPs) and three P53 binding sites have been found in the RAD51 promoter and 5' untranslated region. We hypothesized that RAD51 and P53 SNPs may interact and alter risk of squamous cell carcinoma of the head and neck (SCCHN) and we genotyped for RAD51 135G>C and 172G>T and P53 Arg72Pro SNPs in 716 SCCHN patients and 719 matched controls (all non-Hispanic whites) and evaluated their effects on gamma radiation-induced mutagen sensitivity. We found that RAD51 172TT homozygotes had a significantly decreased risk [adjusted odds ratio (OR) = 0.66, 95% confidence interval (CI) = 0.50-0.87] of SCCHN, compared with carriers of other genotypes, particularly in P53 Arg72Arg homozygotes (adjusted OR = 0.60, 95% CI = 0.41-0.89) (homogeneity test P = 0.047), although no alterations in the risk were associated with the RAD51 135G>C and P53 Arg72Pro SNPs. Consistent with a protective effect of the 172TT genotype, significantly fewer gamma radiation-induced chromatid breaks per cell were present in 172TT homozygotes (mean +/- SD = 0.36 +/- 0.13) than in subjects with other genotypes (mean +/- SD = 0.46 +/- 0.13, P < 0.001) among 148 control subjects we tested. The finding that the functional RAD51 172G>T SNP, particularly in the presence of the P53 Arg72Arg genotype, may be a marker of susceptibility to SCCHN needs to be validated by larger studies of different ethnic populations.
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PMID:172G>T variant in the 5' untranslated region of DNA repair gene RAD51 reduces risk of squamous cell carcinoma of the head and neck and interacts with a P53 codon 72 variant. 1711 68

Tumor suppressor gene BRCA1 is frequently mutated in familial breast and ovarian cancer. BRCA1 plays pivotal roles in maintaining genomic stability by interacting with numerous proteins in cell cycle control and DNA repair. Irofulven (6-hydroxymethylacylfulvene, HMAF, MGI 114, NSC 683863) is one of a new class of anticancer agents that are analogs of mushroom-derived illudin toxins. Preclinical studies and clinical trials have demonstrated that irofulven is effective against several tumor cell types. The exact nature of irofulven-induced DNA damage is not completely understood. We demonstrated previously that irofulven activates ATM and its targets, NBS1, SMC1, CHK2, and p53. In this study, we hypothesize that irofulven induces DNA double-strand breaks and that BRCA1 may affect chemosensitivity by controlling cell cycle checkpoints, DNA repair, and genomic stability in response to irofulven treatment. We observed that irofulven induces the formation of chromosome breaks and radials and the activation and foci formation of gamma-H2AX, BRCA1, and RAD51. We also provided evidence that irofulven induces the generation of DNA double-strand breaks. By using BRCA1-deficient or -proficient cells, we demonstrated that in response to irofulven, BRCA1 contributes to the control of S and G(2)/M cell cycle arrest and is critical for repairing DNA double-strand breaks and for RAD51-dependent homologous recombination. Furthermore, we found that BRCA1 deficiency results in increased chromosome damage and chemosensitivity after irofulven treatment.
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PMID:BRCA1 contributes to cell cycle arrest and chemoresistance in response to the anticancer agent irofulven. 1722 70

p53 is a critical mediator of cellular responses to a variety of stresses. Given the frequency of p53 mutations in human malignancies and that disruption of p53 has been implicated in chemoresistance, understanding the factors that select for p53 disruption is important both for understanding tumor evolution and for designing cancer therapies. While it is widely believed that genotoxic stress selects for p53 mutations, the effects of DNA damaging agents on long-term proliferative potential are usually not affected by p53 status. Previous reports have demonstrated that despite being activated, p53 loss does not prevent cell cycle arrest and senescence in response to high levels of acute replicational stress. In contrast, we recently reported that chronic exposure of non-transformed cells to low, clinically relevant levels of replicational stress induces p53-dependent senescence-like arrest. Disruption of p53 or its target gene p21(CIP1) antagonizes this arrest, leading to a long-term proliferative advantage. However, when replicational stress is associated with substantial DNA strand breaks, the ability of p53 disruption to up-regulate RAD51 dependent homologous recombination becomes important. Replicational stress is induced by many chemotherapeutic treatments and perhaps by some dietary deficiencies, and may be an important factor that selects for p53 mutations during cancer initiation and progression.
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PMID:Replicational stress selects for p53 mutation. 1778 47

Functional loss of both alleles of the breast cancer susceptibility gene, BRCA2, facilitates tumorigenesis. However, the direct effects of BRCA2 heterozygosity remain unclear. Here, BRCA2 heterozygosity was mimicked in HT-29 colon cells by reducing levels of BRCA2 through stable RNA interference. No difference in RAD51 subcellular localization and focus formation was observed between control and mimicked heterozygous cell lines. DNA repair ability, as measured by colony survival following mitomycin C treatment and ultraviolet radiation exposure, was also unaffected by reduced levels of BRCA2. Interestingly, the growth rate of the mimicked BRCA2 heterozygous cell line was significantly lower than that of control cells. Increased expression of p53 in the mimicked heterozygous cells was observed, perhaps in response to BRCA2 deficiency. Levels of p27 were also found to be slightly increased in cells with reduced BRCA2, perhaps contributing to the slower growth rate. Overall, these results suggest that tumors are unlikely to arise directly from BRCA2 heterozygous cells without other genetic events such as loss of the wild-type BRCA2 allele and/or loss of p53 function or other cell cycle inhibitors.
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PMID:DNA damage repair is unaffected by mimicked heterozygous levels of BRCA2 in HT-29 cells. 1794 Jun 34


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