Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The propensity of a cell to undergo apoptosis has been proposed to be a determinant for chemotherapy sensitivity that is not directly dependent on specific drug-target interactions. Androgen-independent prostate cancer is typically refractory to cytotoxic drugs, and we tested whether this is due to a loss of the ability to undergo apoptosis. Exposure of the hormone-insensitive and p53-negative human prostate carcinoma cell line PC-3 to 22 microM cisplatin, 1 microM camptothecin, 10 microM tenoposide, 135 nM vincristine, or 10 microM lovastatin for 72 h caused cell death, internucleosomal DNA fragmentation, and morphological changes typical for apoptosis. One microM cycloheximide prevented anticancer drug-induced apoptosis, whereas high concentration (1 mM) of cycloheximide alone induced apoptosis, indicating that protein synthesis was not needed for these cells to undergo apoptosis. Since cycloheximide affected DNA synthesis and proliferation of PC-3 cells, we tested whether the DNA polymerase inhibitor aphidicolin could also suppress drug-induced apoptosis. In contrast to cycloheximide, aphidicolin inhibited only vincristine-induced apoptosis. Cycloheximide prevented drug-induced changes in cell cycle distribution except for vincristine, while aphidicolin led to an accumulation of cells at the G1-S border independent of the drug used. These data indicate that macromolecular synthesis, active cell cycling, and p53 expression are not required for apoptosis to proceed in this system.
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PMID:Drug-induced apoptosis is not necessarily dependent on macromolecular synthesis or proliferation in the p53-negative human prostate cancer cell line PC-3. 774 12

DNA polymerase beta is a nuclear protein essential to DNA repair in mammalian cells. A high frequency of mutations in this gene has been reported in colorectal cancers. To clarify the tumorigenesis steps of human prostate cancers in the molecular basis, we examined the entire coding region of the human DNA polymerase beta gene in human prostate cancer tissues using polymerase chain reaction, single-strand conformational polymorphism analysis of RNA, and sequencing analysis. Consequently, we detected DNA polymerase beta gene mutations in 2 of 12 cases (17%). The first case is an A to G transition at nucleotide 893, resulting in a substitution of the amino acid from tyrosine to cysteine. In the second case, we found an A to G transition at nucleotide 305, a T deletion at nucleotide 569, and an A insertion into the 6 repeats of A from nucleotide 612 to 617. This T deletion shifted the subsequent reading frame and resulted in the premature termination at codon 163 instead of 336. The two cases were advanced grade and stage. Present results suggest that polymerase beta gene mutations, although they occurred at relatively low frequency, are involved in certain cases of human prostate carcinogenesis.
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PMID:DNA polymerase beta gene mutation in human prostate cancer. 818 60

We examined 24 human bladder cancer tissues for possible mutations in the entire coding region of the human DNA polymerase beta gene using polymerase chain reaction analysis, single-strand conformational polymorphism analysis of RNA, and sequence analysis. DNA polymerase beta gene mutations were observed in four of the 24 cases (16.7%) and included three missense point mutations and a single base insertion. The single base insertion was also observed in our previous study of human prostate cancer, suggesting that this region may be a hot spot for mutation of the DNA polymerase beta gene. No clinical or pathological association was found among the four cases that contained the mutation. Three of the four cases with DNA polymerase beta gene mutation had mutations of the p16 or RB genes or loss of heterozygosity of the p53 and APC gene loci. The results of the study presented here suggest that DNA polymerase beta gene mutations, in combination with mutations of tumor suppressor genes, may be involved in certain cases of human bladder cancer.
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PMID:DNA polymerase beta gene mutations in human bladder cancer. 856 64

The 39-kDa DNA polymerase beta (pol beta) is an essential enzyme in short-patch base excision repair pathway. A wild-type and a truncated forms of pol beta proteins are expressed in primary colorectal and breast adenocarcinomas and in a primary culture of renal cell carcinoma. To test whether pol beta has a contributory role in tumorigenicity of human tumor cell lines, we have undertaken a study to determine expression of pol beta in colon, breast, and prostate tumor cell lines. Unlike primary colon tumor cells, three types of pol beta mRNA have been identified in HCT116, LoVo, and DLD1, colon tumor cell lines. A 111-bp-deleted pol beta transcript was expressed in MCF7, a breast tumor cell line, but not in primary breast tumor cells. An expression of a smaller pol beta transcript has been revealed in DU145, a prostate tumor cell line, whereas, a single base (T) deletion in mRNA at codon 191 was found in prostate cancer tissue. Interestingly, a wild-type pol beta transcript was also expressed in all tumor cell lines similar to primary tumor cells. Furthermore, the cell extract of LoVo exhibited highest gap-filling synthesis function of pol beta when the extract of DU145 showed lowest activity. MNNG, a DNA alkylating agent, enhanced the gap-filling synthesis activity in extracts of LoVo cell line. Furthermore, the cellular viability of LoVo and HCT116 cells is sensitive to MNNG when DU145 cells are resistant. These results demonstrate heterogeneity in pol beta mRNA expression, which may be a risk factor related to tumorigenic activities of tumor cell lines.
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PMID:Heterogeneity in expression of DNA polymerase beta and DNA repair activity in human tumor cell lines. 1206 74

Together with cell cycle checkpoint control, DNA repair plays a pivotal role in protecting the genome from endogenous and exogenous DNA damage. Although increased genetic instability has been associated with prostate cancer progression, the relative role of DNA double-strand break repair in malignant versus normal prostate epithelial cells is not known. In this study, we determined the RNA and protein expression of a series of DNA double-strand break repair genes in both normal (PrEC-epithelial and PrSC-stromal) and malignant (LNCaP, DU-145, and PC-3) prostate cultures. Expression of genes downstream of ATM after ionizing radiation-induced DNA damage reflected the p53 status of the cell lines. In the malignant prostate cell lines, mRNA and protein levels of the Rad51, Xrcc3, Rad52, and Rad54 genes involved in homologous recombination were elevated approximately 2- to 5-fold in comparison to normal PrEC cells. The XRCC1, DNA polymerase-beta and -delta proteins were also elevated. There were no consistent differences in gene expression relating to the nonhomologous end-joining pathway. Despite increased expression of DNA repair genes, malignant prostate cancer cells had defective repair of DNA breaks, alkali-labile sites, and oxidative base damage. Furthermore, after ionizing radiation and mitomycin C treatment, chromosomal aberration assays confirmed that malignant prostate cells had defective DNA repair. This discordance between expression and function of DNA repair genes in malignant prostate cancer cells supports the hypothesis that prostate tumor progression may reflect aberrant DNA repair. Our findings support the development of novel treatment strategies designed to reinstate normal DNA repair in prostate cancer cells.
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PMID:Defective DNA strand break repair after DNA damage in prostate cancer cells: implications for genetic instability and prostate cancer progression. 1557 58

As part of a systematic study of the effects of phytochemicals beyond antioxidation on cancer prevention, we investigated whether naringenin (NR), a citrus flavonoid, stimulates DNA repair following oxidative damage in LNCaP human prostate cancer cells. The 8-hydroxydeoxyguanosine (8-OH-dG) to deoxyguanosine (dG) ratio was measured after cells were treated with 200 micromol/L of ferrous sulfate in serum-free medium followed by NR exposure for 24 h in growth medium. The results demonstrated that exposure to 10-80 micromol/L of NR led to a significant decrease in the ratio of 8-OH-dG to 10(6) dG. Because cells were treated with NR after ferrous sulfate was removed, we conclude that we demonstrated an effect on DNA repair beyond antioxidation. In support of this conclusion, we determined the induction of mRNA expression over time after oxidative stress followed by NR administration of three major enzymes in the DNA base excision repair (BER) pathway: 8-oxoguanine-DNA glycosylase 1 (hOGG1), apurinic/apyrimidinic endonuclease and DNA polymerase beta (DNA poly beta). hOGG1 and DNA poly beta mRNA expression in cells after 24-h exposure to NR was increased significantly compared with control cells without NR. The intracellular concentration of NR after exposure to 80 micromol/L was 3 pmol/mg protein, which is physiologically achievable in tissues. In conclusion, the cancer-preventive effects of citrus fruits demonstrated in epidemiological studies may be due in part to stimulation of DNA repair by NR, which by stimulating BER processes may prevent mutagenic changes in prostate cancer cells.
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PMID:The citrus flavonoid naringenin stimulates DNA repair in prostate cancer cells. 1611 81

Telomeres are terminal, repeated deoxyribonucleic acid (DNA) sequences that stabilize and protect the ends of the chromosomes. Mounting evidence indicates that by initiating chromosomal instability, short dysfunctional telomeres may be involved in prostate carcinogenesis. Although the exact cause of the telomere shortening observed in prostate cancer remains a mystery, telomere loss is known to occur during cell division and oxidative DNA damage, 2 byproducts of chronic inflammation, which is a common histologic finding in the prostate. In addition to prostate cancer causation, telomeres may also play a role in disease progression, and there are indications that tumor telomere content may prove useful as a prognostic marker. Once established, prostate cancer cells almost invariably activate the telomeric DNA polymerase enzyme telomerase, the detection of which may prove useful for diagnostic purposes. Interestingly, telomerase activity is suppressed in prostate cancer cells after androgen withdrawal, raising the possibility that androgen ablative therapies may re-instigate telomere loss, and consequent genetic instability, in surviving cancer cells, thus contributing to the emergence of an androgen-independent, lethal phenotype. A more thorough understanding of telomere biology as it relates to prostate cancer should provide new opportunities for disease prevention, diagnosis, prognostication, and treatment.
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PMID:Telomeres and telomerase in prostatic intraepithelial neoplasia and prostate cancer biology. 1652 Feb 76

Somatic mutations are hallmarks of cancer progression. We sequenced 26 matched human prostate tumor and constitutional DNA samples for somatic alterations in the SRD5A2, HPRT, and HSD3B2 genes, and identified 71 nucleotide substitutions. Of these substitutions, 79% (56/71) occur within a WKVnRRRnVWK sequence (a novel motif we call THEMIS [from the ancient Greek goddess of prophecy]: W=A/T, K=G/T, V=G/A/C, R=purine (A/G), and n=any nucleotide), with one mismatch allowed. Literature searches identified this motif with one mismatch allowed in 66% (37/56) of the somatic prostate cancer mutations and in 74% (90/122) of the somatic breast cancer mutations found in all human genes analyzed. We also found the THEMIS motif with one allowed mismatch in 88% (23/26) of the ras1 gene somatic mutations formed in the sensitive to skin carcinogenesis (SENCAR) mouse model, after induction of error-prone DNA repair following mutagenic treatment. The high prevalence of the motif in each of the above mentioned cases cannot be explained by chance (P<0.046). We further identified 27 somatic mutations in the error-prone DNA polymerase genes pol eta, pol kappa, and pol beta in these prostate cancer patients. The data suggest that most somatic nucleotide substitutions in human cancer may occur in sites that conform to the THEMIS motif. These mutations may be caused by "mutator" mutations in error-prone DNA polymerase genes.
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PMID:Genomic analysis of cancer tissue reveals that somatic mutations commonly occur in a specific motif. 1862 41

We have recently shown that penta-1,2,3,4,6-O-galloyl-beta-D-glucose (PGG), a naturally occurring hydrolyzable gallotannin, inhibited the in vivo growth of human androgen-independent p53-mutant DU145 prostate cancer (PCa) xenograft in athymic nude mice without adverse effect on their body weight. We have also shown that PGG induced caspase-mediated apoptosis in the DU145 cells and the androgen-dependent human p53-wild-type LNCaP cells. Here, we investigated the cell cycle effects of PGG in these and other PCa cells. Our data show that treatment with subapoptotic doses of PGG induced S-arrest, whereas higher doses of PGG induced not only S-arrest but also G(1) arrest. We show, for the first time, that irrespective of the p53 functional status of the PCa cell lines, PGG exerted a rapid (within 2 h) and potent inhibition (inhibitory concentration by 50% approximately 6 microM) of 5-bromo-2'-deoxyuridine incorporation into S phase cells. In isolated nuclei, PGG inhibited DNA replicative synthesis with superior efficacy than a known DNA polymerase alpha inhibitor, aphidocolin. In addition to the S-arrest action, we have found a close association of downregulation of cyclin D1 with G(1) arrest induced by PGG. Overexpressing this G(1) cyclin abolished G(1) arrest, but hastened the S-arrest induction by PGG. Together, our data indicate that PGG induced PCa S-arrest probably through DNA replicative blockage and induced G(1) arrest via cyclin D1 downregulation to contribute to anticancer activity. Our data raise the hypothesis that PGG may be a novel inhibitor of DNA polymerases.
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PMID:Penta-O-galloyl-beta-D-glucose induces S- and G(1)-cell cycle arrests in prostate cancer cells targeting DNA replication and cyclin D1. 1926 99

In 2006, sequences described as xenotropic murine leukemia virus-related virus (XMRV) were discovered in prostate cancer patients. In October 2009, we published the first direct isolation of infectious XMRV from humans and the detection of infectious XMRV in patients with chronic fatigue syndrome. In that study, a combination of classic retroviral methods were used including: DNA polymerase chain reaction and reverse transcriptase polymerase chain reaction for gag and env, full length genomic sequencing, immunoblotting for viral protein expression in activated peripheral blood mononuclear cells, passage of infectious virus in both plasma and peripheral blood mononuclear cells to indicator cell lines, and detection of antibodies to XMRV in plasma. A combination of these methods has since allowed us to confirm infection by XMRV in 85% of the 101 patients that were originally studied. Since 2009, seven studies, predominantly using DNA polymerase chain reaction of blood products or tumor tissue, have reported failures to detect XMRV infection in patients with either prostate cancer or chronic fatigue syndrome. A review of the current literature on XMRV supports the importance of applying multiple independent techniques in order to determine the presence of this virus. Detection methods based upon the biological and molecular amplification of XMRV, which is usually present at low levels in unstimulated blood cells and plasma, are more sensitive than assays for the virus by DNA polymerase chain reaction of unstimulated peripheral blood mononuclear cells. When we examined patient blood samples that had originally tested negative by DNA polymerase chain reaction by more sensitive methods, we observed that they were infected with XMRV; thus, the DNA polymerase chain reaction tests provided false negative results. Therefore, we conclude that molecular analyses using DNA from unstimulated peripheral blood mononuclear cells or from whole blood are not yet sufficient as stand-alone assays for the identification of XMRV-infected individuals. Complementary methods are reviewed, that if rigorously followed, will likely show a more accurate snapshot of the actual distribution of XMRV infection in humans.
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PMID:Distribution of xenotropic murine leukemia virus-related virus (XMRV) infection in chronic fatigue syndrome and prostate cancer. 2084 3


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