Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cdk-interacting protein 1 (Cip1) is a p53-regulated 21-kDa protein that inhibits several members of the cyclin-dependent kinase (CDK) family. It was initially observed in complexes containing CDK4, cyclin D, and proliferating cell nuclear antigen (PCNA). PCNA, in conjunction with activator 1, acts as a processivity factor for eukaryotic DNA polymerase (pol) delta, and these three proteins constitute the pol delta holoenzyme. In this report, we demonstrate that Cip1 can also directly inhibit DNA synthesis in vitro by binding to PCNA. Cip1 efficiently inhibits simian virus 40 replication dependent upon pol alpha, activator 1, PCNA, and pol delta, and this inhibition can be overcome by additional PCNA. Simian virus 40 DNA replication, catalyzed solely by high levels of pol alpha-primase complex, is unaffected by Cip1. Using the surface plasmon resonance technique, a direct physical interaction of PCNA and Cip1 was detected. We have observed that Cip1 efficiently inhibits synthesis of long (7.2 kb) but not short (10 nt) templates, suggesting that its association with PCNA is likely to impair the processive movement of pol delta during DNA chain elongation, as opposed to blocking assembly of the pol delta holoenzyme. The implications of the Cip1-PCNA interaction with respect to regulation of DNA synthesis, cell cycle checkpoint control, and DNA repair are discussed.
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PMID:Cdk-interacting protein 1 directly binds with proliferating cell nuclear antigen and inhibits DNA replication catalyzed by the DNA polymerase delta holoenzyme. 791 43

Small DNA viruses are dependent on the interaction of early proteins (such as large T antigen) with host p53 and Rb to bring about the G1-to-S cell cycle transition. The large DNA viruses are less dependent on host regulatory genes since additional early viral proteins (such as viral DNA polymerase, DNA metabolic enzymes, and other replication proteins) are involved in DNA synthesis. A highly conserved domain of large T antigen (similar to the p53-binding region) exclusively identifies papovavirus, parvovirus, and papillomaviruses from all other larger DNA viruses and implies a conserved interaction with host regulatory genes. In this report, we show that 3 to 6 mM butyrate, a general cell cycle blocker implicated in inhibition of the G1-to-S transition, inhibits DNA replication of polyomavirus and human papillomavirus type 11 but not the replication of larger DNA viruses such as adenovirus types 2 and 5, herpes simplex virus type 1, Epstein-Barr virus, and cytomegalovirus, which all bypass the butyrate-mediated cell cycle block. This butyrate effect on polyomavirus replication is not cell type specific, nor does it depend on the p53 or Rb gene, as inhibition was seen in fibroblasts with intact or homozygous deleted p53 or Rb, 3T6 cells, keratinocytes, C2C12 myoblasts, and 3T3-L1 adipocytes. In addition, butyrate did not inhibit expression of polyomavirus T antigen. The antiviral effect of butyrate involves a form of imprinted state, since pretreatment of cells with 3 mM butyrate inhibits human papillomavirus type 11 DNA replication for at least 96 h after its removal. Butyrate, therefore, serves as a molecular tool in dissecting the life cycle of smaller DNA viruses from that of the larger DNA viruses in relation to the cell cycle.
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PMID:n-Butyrate, a cell cycle blocker, inhibits the replication of polyomaviruses and papillomaviruses but not that of adenoviruses and herpesviruses. 803 79

Exposure of normal adult human skin to doses of UV irradiation that induced mild sunburn resulted in the rapid appearance of p53 protein in the epidermis and superficial dermal fibroblasts. Immunohistological analysis with a panel of antibodies established that while p53 staining was not seen in normal skin it appeared within 2 h of UV exposure. The level of p53 immunostaining peaked at 24 h and returned to undetectable levels within 360 h. The induction of proliferating cell nuclear antigen (PCNA) (which is required for both DNA replication and repair) followed a similar spatial and temporal pattern to p53. The UV irradiation did not induce a mitotic response or the replication-associated antigens DNA polymerase alpha or Ki67. The accumulation of high levels of p53 and PCNA in response to UV doses to which many human populations are routinely exposed provides strong support for a model in which normal p53 acts as part of the DNA damage response in vertebrate cells. Such a model is consistent with the profound tumour-suppressor function of the p53 gene, the high rate of p53 mutation in neoplasia and the exceptionally high tumour susceptibility of p53-deficient mice.
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PMID:High levels of p53 protein in UV-irradiated normal human skin. 809 10

The tumour suppressor p53 specifically interferes with the onset of S phase. The mechanism of the growth suppression action of the protein is unclear, though recent evidence points to transcriptional activation and repression functions of the protein. A competing hypothesis suggests that p53 interacts with the DNA replication apparatus and directly interferes with DNA replication. The major evidence for this hypothesis is that p53 interacts with the simian virus 40 (SV40)-encoded protein T antigen and interferes with the ability of T antigen to unwind the SV40 origin of DNA replication, and recruit DNA polymerase alpha to the replication initiation complex. Here we report that p53 physically interacts with and inhibits the function of a cellular DNA replication factor, the single-stranded DNA-binding protein complex RPA.
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PMID:Inhibition of DNA replication factor RPA by p53. 836 31

By immunoprecipitation analysis, enhanced p53 expression was detected in 3 of 4 adult T-cell leukemia (ATL) cell lines, 1 of 3 HTLV-I-infected cell lines and 1 of 5 fresh ATL samples, compared with phytohemagglutinin-stimulated peripheral blood lymphocytes. Among these 5 high expressers, p53 missense mutations were indicated in 2 ATL cell lines and 1 fresh ATL sample by extensive p53 cDNA and genomic DNA polymerase chain reaction single-strand conformation polymorphism analysis. No mutation was found throughout the entire coding region of the remaining 2 high expressers (1 ATL and 1 HTLV-I-infected cell lines) and low expressers of p53 (2 HTLV-I-infected cell lines). Tax oncoprotein expression was found in these 2 high p53 expressers in which p53 mutation was not present, but not in low p53 expressers or cells carrying this mutation. The levels of p53 mRNA were similar among the samples regardless of p53 levels. Posttranscriptional mechanisms other than missense mutation would thus appear to increase p53 in the Tax-expressing cells but not in cells containing undetectable levels of Tax. No complex formation between p53 and Tax was observed.
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PMID:Aberrant expression of the p53 tumor suppressor gene in adult T-cell leukemia and HTLV-I-infected cells. 844 26

Many transcription factors can activate the initiation of DNA replication. We have used affinity chromatography to show that the acidic activation domains of the transcription factors VP16, GAL4, and p53 each bind selectively to human and yeast replication factor A (RPA). The binding is direct and to the largest subunit of the trimeric RPA complex, RPA-1. Mutations in VP16 that reduce the ability of GAL4-VP16 to activate polyomavirus DNA replication also compromise the binding of VP16 to RPA. We suggest that transcription factors may interact with RPA either to stabilize single-stranded DNA at a replication origin or to recruit DNA polymerase alpha to the replication initiation complex.
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PMID:The transactivator proteins VP16 and GAL4 bind replication factor A. 851 4

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

We have developed a fluorescence-based single-strand conformation polymorphism analysis to detect Haelil-sensitive polymorphic sites in intron 1 of the TP53 gene. It is important to treat the PCR products with Klenow fragment to remove a 3'-protruding nucleotide from the amplified DNA fragments added during the reaction in order to obtain a single peak for each allele. A comparison of the signal profiles of two alleles with those of normal heterozygotes by data processing using computer software has enabled sensitive detection of loss of heterozygosity (LOH) from clinical materials with a fraction of tumor cells below 10%. In analysis of 14 pancreatic carcinomas in which the proportion of the tumor cells is usually low due to the abundance of the stromal component, 7 samples (50%) were informative and 5 of the 7 (71.4 %) were positive for LOH at the TP53 locus. This approach would be useful for allelotyping tumors with low cellularity, as well as other clinical samples such as biopsied specimens and paraffin embedded tissues.
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PMID:Sensitive detection of loss of heterozygosity in the TP53 gene in pancreatic adenocarcinoma by fluorescence-based single-strand conformation polymorphism analysis using blunt-end DNA fragments. 872 79

High levels of bcl-2 protein have been found in a wide variety of human cancers. Since p53 gene inactivation occurs in over half of human cancers, it is possible that loss of p53-mediated repression of bcl-2 gene expression accounts, at least in part, for the frequent abnormalities in bcl-2 protein production seen in tumours. By using immunohistochemical methods, we have analysed thirty-three nasopharyngeal carcinomas for p53 and bcl-2 expression. We found an inverse correlation between the expression of these two proteins (P < 0.001). Moreover, we utilized universal oligonucleotide primers of a region 5' to the bcl-2 MBR and at the 3' end of JH segments to initiate a DNA polymerase chain reaction that amplified these bcl-2-JH junctures. Of the twelve nasopharyngeal carcinomas expressing bcl-2, none showed a t(14;18) chromosome translocation. These findings may indicate potential mechanisms by which bcl-2 regulates apoptosis.
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PMID:Down regulation of bcl-2 by p53 in nasopharyngeal carcinoma and lack of detection of its specific t(14;18) chromosomal translocation in fixed tissues. 873 40

A retroviral vector containing the wild-type p53 gene under control of a beta-actin promoter was produced to mediate transfer of wild-type p53 into human non-small cell lung cancers by direct injection. Nine patients whose conventional treatments failed were entered into the study. No clinically significant vector-related toxic effects were noted up to five months after treatment. In situ hybridization and DNA polymerase chain reaction showed vector-p53 sequences in posttreatment biopsies. Apoptosis (programmed cell death) was more frequent in posttreatment biopsies than in pretreatment biopsies. Tumor regression was noted in three patients, and tumor growth stabilized in three other patients.
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PMID:Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer. 878 51


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