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)

Cell cycle checkpoints enhance genetic fidelity by causing arrest at specific stages of the cell cycle when previous events have not been completed. The tumor suppressor p53 has been implicated in a G1 checkpoint. To investigate whether p53 also participates in a mitotic checkpoint, cultured fibroblasts from p53-deficient mouse embryos were exposed to spindle inhibitors. The fibroblasts underwent multiple rounds of DNA synthesis without completing chromosome segregation, thus forming tetraploid and octaploid cells. Deficiency of p53 was also associated with the development of tetraploidy in vivo. These results suggest that murine p53 is a component of a spindle checkpoint that ensures the maintenance of diploidy.
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PMID:A p53-dependent mouse spindle checkpoint. 787 34

Deficiency in p53-mediated cell death is common in human cancer, contributing to both tumorigenesis and chemoresistance. In an attempt to restore p53, we evaluated in vitro infectivity and cytotoxicity of a wild type (w.t.) p53-expressing adenovirus (Ad-p53) toward a panel of human cancer cell lines (n = 19). At a multiplicity of infection of 30, both Ad-p53 and adenovirus expressing beta-galactosidase (Ad-LacZ) infected greater than 99% of cells derived from brain, lung, breast, ovarian, colon, and prostate cancer, but failed to infect leukemia or lymphoma cells. Ad-p53, but not Ad-LacZ, infection of cancer cells was followed by nuclear accumulation of the CDK inhibitor p21WAFI/CIPI, cell cycle arrest and loss of viability. Ad-p53 induced apoptotic death in cancer cells that express mutant p53, including multi-drug resistant cells, but fewer deaths were observed in some w.t. p53 expressing cells. Ad-p53-infected SKBr3 breast cancer cells were more sensitive to cytotoxicity of the DNA damaging drugs mitomycin C or Adriamycin, but not the M-phase specific drug vincristine. Our results suggest that Ad-p53 is capable of infecting and killing cancer cells of diverse tissue origins (including multi-drug resistant cancer cells), that p21WAFI/CIPI may be a useful marker of p53 infectivity and that there may be synergy between Ad-p53 and either mitomycin C or Adriamycin induced cell death in tumors with p53 mutations.
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PMID:In vitro evaluation of a p53-expressing adenovirus as an anti-cancer drug. 870 13

Deficiency in genes involved in DNA mismatch repair increases susceptibility to cancer, particularly of the colorectal epithelium. Using Msh2 null mice, we demonstrate that this genetic defect renders normal intestinal epithelial cells susceptible to mutation in vivo at the Dlb-1 locus. Compared with wild-type mice, Msh2-deficient animals had higher basal levels of mutation and were more sensitive to the mutagenic effects of temozolomide. Experiments using Msh2-deficient cells in vitro suggest that an element of this effect is attributable to increased clonogenicity. Indeed, we show that Msh2 plays a role in the in vivo initiation of apoptosis after treatment with temozolomide, N-methyl-N'-nitro-N-nitrosoguanidine, and cisplatin. This was not influenced by the in vivo depletion of O6-alkylguanine-DNA-alkyltransferase after administration of O6-benzylguanine. By analyzing mice mutant for both Msh2 and p53, we found that the Msh2-dependent apoptotic response was primarily mediated through a p53-dependent pathway. Msh2 also was required to signal delayed p53-independent death. Taken together, these studies characterize an in vivo Msh2-dependent apoptotic response to methylating agents and raise the possibility that Msh2 deficiency may predispose to malignancy not only through failed repair of mismatch DNA lesions but also through the failure to engage apoptosis.
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PMID:Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine. 1009 37

We have used spectral karyotyping to assess potential roles of three different components of the nonhomologous DNA end-joining pathway in the maintenance of genomic stability in mouse embryonic fibroblasts (MEFs). MEFs homozygous for mutations that inactivate either DNA ligase IV (Lig4) or Ku70 display dramatic genomic instability, even in the absence of exogenous DNA damaging agents. These aberrant events range from chromosomal fragmentation to nonreciprocal translocations that can involve several chromosomes. DNA-dependent protein kinase catalytic subunit deficiency also promotes genome instability. Deficiency for the p53 cell cycle checkpoint protein has little effect on spontaneous levels of chromosomal instability in Lig4-deficient fibroblasts. However, in the context of ionizing radiation treatment, p53 deficiency allowed visualization of massive acute chromosomal destruction in Lig4-deficient MEFs, which in surviving cells manifested as frequent nonreciprocal translocations. We conclude that nonhomologous DNA end-joining plays a crucial role as a caretaker of the mammalian genome, and that an alternative repair pathway exists that often leads to nonreciprocal translocations.
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PMID:The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations. 1082 7

Mechanisms of carcinogenesis through abnormalities of DNA repair genes are overviewed. Inactivation of DNA mismatch repair(MMR) gene(s) observed in tumors of hereditary non-polyposis colorectal cancer induces frameshift mutator mutation in MMR genes themselves, growth inhibitory genes and apoptosis inhibitory genes providing favorable genetic background for a malignant clone to be expanded. Deficiency of nucleotide excision repair that is usually employed for the removal of pyrimidine dimer formed by ultraviolet-irradiation in xeroderma pigmentosum (XP) causes hypersensitivity of the skin to sunlight as well as increased risk of skin cancer. Strand specificity and absence of hot spots for p53 tumor suppressor gene mutations was reported in ultraviolet induced skin cancers of XP model mice.
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PMID:[Carcinogenesis through abnormalities of DNA repair genes]. 1087 47

Deficiency of folate or vitamin B(12) (cobalamin) causes megaloblastic anemia, a disease characterized by pancytopenia due to the excessive apoptosis of hematopoietic progenitor cells. Clinical and experimental studies of megaloblastic anemia have demonstrated an impairment of DNA synthesis and repair in hematopoietic cells that is manifested by an increased percentage of cells in the DNA synthesis phase (S phase) of the cell cycle, compared with normal hematopoietic cells. Both folate and cobalamin are required for normal de novo synthesis of thymidylate and purines. However, previous studies of impaired DNA synthesis and repair in megaloblastic anemia have concerned mainly the decreased intracellular levels of thymidylate and its effects on nucleotide pools and misincorporation of uracil into DNA. An in vitro model of folate-deficient erythropoiesis was used to study the relationship between the S-phase accumulation and apoptosis in megaloblastic anemia. The results indicate that folate-deficient erythroblasts accumulate in and undergo apoptosis in the S phase when compared with control erythroblasts. Both the S-phase accumulation and the apoptosis were induced by folate deficiency in erythroblasts from p53 null mice. The complete reversal of the S-phase accumulation and apoptosis in folate-deficient erythroblasts required the exogenous provision of specific purines or purine nucleosides as well as thymidine. These results indicate that decreased de novo synthesis of purines plays as important a role as decreased de novo synthesis of thymidylate in the pathogenesis of megaloblastic anemia.
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PMID:Apoptosis in megaloblastic anemia occurs during DNA synthesis by a p53-independent, nucleoside-reversible mechanism. 1105 10

Deficiency in a helicase of the RecQ family is found in at least three human genetic disorders associated with cancer predisposition and/or premature ageing. The RecQ helicases encoded by the BLM, WRN and RECQ4 genes are defective in Bloom's, Werner's and Rothmund-Thomson syndromes, respectively. Cells derived from individuals with these disorders in each case show inherent genomic instability. Recent studies have demonstrated direct interactions between these RecQ helicases and human nuclear proteins required for several aspects of chromosome maintenance, including p53, BRCA1, topoisomerase III, replication protein A and DNA polymerase delta. Here, we review this network of protein interactions, and the clues that they present regarding the potential roles of RecQ family members in DNA repair, replication and/or recombination pathways.
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PMID:DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. 1125 7

The present study assessed the role of adenoviral vector-mediated wild-type p53 gene transfer in B lymphoma cells. Deficiency of p53-mediated cell death is common in human cancer contributing to both tumorigenesis and chemoresistance. Lymphoma cells are being considered as suitable targets for gene therapy protocols. Recently, we reported an adenoviral protocol leading to highly efficient gene transfer to B lymphoma cells. All lymphoma cell lines (n=5) tested here showed mutations in the p53 gene locus. The aim of this work was to transduce lymphoma cells with the wild-type p53 gene. Using this protocol, 88% of Raji, 75% of Daudi, and 45% of OCI-Ly8-LAM53 cells were transfected with the reporter gene green fluorescent protein at a multiplicity of infection of 200. The expression of green fluorescent protein in CA46 and BL41 cells was 27% and 42%, respectively. At this multiplicity of infection, growth characteristics of lymphoma cell lines were not changed significantly. In contrast, cells transduced with wild-type p53 gene showed an inhibition of proliferation as well as an increase in apoptosis. Cell loss by apoptosis after p53 gene transfer was up to 40% as compared to transduction with an irrelevant vector. In addition, we determined the effects of DNA damage produced by the DNA topoisomerase II inhibitor etoposide on wild-type p53 transfected lymphoma cells. In Ad-p53-transfected Raji cells, treatment with the drug resulted in a marked increase of cell loss in comparison to Ad-beta-Gal-transfected cells (45% vs. 77%). Interestingly, performing cytotoxicity studies, we could show an increased sensitivity of Raji and Daudi cells against immunological effector cells. In conclusion, transduction of wild-type p53 into lymphoma cells expressing mutated p53 was efficient and led to inhibition of proliferation and increase in apoptotic rate in some cell lines dependent on p53 mutation. This protocol should have an impact on the use of lymphoma cells in cancer gene therapy protocols.
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PMID:Effects of adenoviral wild-type p53 gene transfer in p53-mutated lymphoma cells. 1149 63

Multi-drug resistance can be induced by various environmental stresses including an exposure to chemical drugs and X-ray irradiation. In addition, hypo-nutritive conditions are known to promote multi-drug resistance in solid tumours. To understand the importance of nutritive conditions in the development of drug resistance in non-solid tumours and to know whether a transient malnutrition could induce a permanent reduction in drug sensitivity, leukaemic cells were transiently cultured under growth factor-starved conditions. Granulocyte-macrophage colony-stimulating factor-dependent human leukaemic MO7e cells were cultured in the absence of granulocyte-macrophage colon-stimulating factor for 2 weeks, during which the majority of the cells died, and the minor viable cells were expanded in the presence of granulocyte-macrophage colon-stimulating factor for following 1 week. This procedure was repeated three times, and the surviving cells were cloned by limiting dilution. These clones underwent G1 arrest in the absence of granulocyte-macrophage colon-stimulating factor, while parental cells underwent apoptosis. Interestingly, activities of the downstream targets of granulocyte-macrophage colon-stimulating factor receptor were regulated in a granulocyte-macrophage colon-stimulating factor-independent manner, indicating that the ligand-independent activation of granulocyte-macrophage colon-stimulating factor receptor had not taken place. Moreover, the 4--7-fold increases in IC(50) for etoposide and the 2--6-fold increase in IC(90) for doxorubicin was observed. Furthermore, Bcl-2 protein expression was significantly up-regulated in the clones while no significant changes in Bax, Bcl-(xL), P-glycoprotein and Hsp70 protein expression and no consistent changes in p53 expression were detected. We propose that recurrent growth factor starvation, which may occur in vivo when stromal function is damaged after intensive chemotherapy or bone marrow occupation by malignant cells, causes selection of drug resistant leukaemia cells that will expand when the growth factor supply recovers.
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PMID:Recurrent growth factor starvation promotes drug resistance in human leukaemic cells. 1187 May 22

Skeletal muscle atrophy is a common feature in alcoholism that affects up to two-thirds of alcohol misusers, and women appear to be particularly susceptible. There is also some evidence to suggest that malnutrition exacerbates the effects of alcohol on muscle. However, the mechanisms responsible for the myopathy remain elusive, and some studies suggest that acetaldehyde, rather than alcohol, is the principal pathogenic perturbant. Previous reports on rats dosed acutely with ethanol (<24 h) have suggested that increased proto-oncogene expression (i.e., c-myc) may be a causative process, possibly via activating preapoptotic or transcriptional pathways. We hypothesized that 1) increases in c-myc mRNA levels also occur in muscle exposed chronically to alcohol, 2) muscle of female rats is more sensitive than that from male rats, 3) raising acetaldehyde will also increase c-myc, 4) prior starvation will cause further increases in c-myc mRNA expression in response to ethanol, and 5) other genes involved in apoptosis (i.e., p53 and Bcl-2) would also be affected by alcohol. To test this, we measured c-myc mRNA levels in skeletal muscle of rats dosed either chronically (6-7 wk; ethanol as 35% of total dietary energy) or acutely (2.5 h; ethanol as 75 mmol/kg body wt ip) with ethanol. All experiments were carried out in male Wistar rats (approximately 0.1-0.15 kg body wt) except the study that examined gender susceptibility in male and female rats. At the end of the studies, rats were killed, and c-myc, p53, and Bcl-2 mRNA was analyzed in skeletal muscle by RT-PCR with an endogenous internal standard, GAPDH. The results showed that 1) in male rats fed ethanol chronically, there were no increases in c-myc mRNA; 2) increases, however, occurred in c-myc mRNA in muscle from female rats fed ethanol chronically; 3) raising endogenous acetaldehyde with cyanamide increased c-myc mRNA in acute studies; 4) starvation per se increased c-myc mRNA levels and at 1 day potentiated the acute effects of ethanol, indicative of a sensitization response; 5) the only effect seen with p53 mRNA levels was a decrease in muscle of rats starved for 1 day compared with fed rats, and there was no statistically significant effect on Bcl-2 mRNA in any of the experimental conditions. The increases in c-myc may well represent a preapoptotic effect, or even a nonspecific cellular stress response to alcohol and/or acetaldehyde. These data are important in our understanding of a common muscle pathology induced by alcohol.
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PMID:Acute and chronic effects of alcohol exposure on skeletal muscle c-myc, p53, and Bcl-2 mRNA expression. 1287 71


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