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)

One of the sulfo-lipids, 1-mono-O-acyl-3-O-(alpha-D-sulfoquinovosyl)-glyceride (SQMG), potently and selectively inhibited the activity of mammalian DNA polymerases. SQMG was also a potent apoptosis inducer and the SQMG effect occurred through the induction of G1 arrest with a reduction in the proportion of cells in the S phase. SQMG clearly increased the levels of p53 and p21 proteins, but did not induce the expression of p27 and p16 proteins. SQMG markedly reduced the pRb protein level and inhibited pRb phosphorylation after 48hr. These results suggested that SQMG activates the G1 checkpoint as a result of the DNA polymerase inhibition, and then promotes a p53-dependent apoptotic response. Since aphidicolin, a well-known replicative DNA polymerase inhibitor, did not promote these protein expressions, the apoptosis-inducing pathway by SQMG differs from that by aphidicolin.
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PMID:Analysis of cell cycle regulation by 1-mono-O-acyl-3-O-(alpha-D-sulfoquinovosyl)-glyceride (SQMG), an inhibitor of eukaryotic DNA polymerases. 1290 19

It would be advantageous to measure mutation load in situ in order to determine the relationship between a high mutation load and increased risk for cancer or other diseases and to evaluate sources of possible mutagen exposure. Previously, in situ mutation detection assays have been plagued with multiple rounds of amplification and high rates of false-positives and false-negatives. The single cell immunohistochemical mutation load assay (SCIMLA) was developed to measure somatic mutation frequency, pattern, and spectrum in normal tissues with a single round of amplification. The P53 gene was utilized as a mutation reporter because of the unusual property that missense mutations often cause P53 protein to accumulate in the cell, allowing the mutant proteins to be detected by immunohistochemical staining. Alternative reporter genes with stabilized mutant proteins may be envisioned. Single cells that stain positively for P53 protein overabundance (red cells) were microdissected from ethanol-fixed and paraffin-embedded tissues. A novel stimulated-PCR (S-PCR) protocol permitted successful amplification of a 1.8-kb segment of the P53 gene (i.e., exons 5-9) in 87% of single mammary cells. Subsequent sequence analysis demonstrated that 35% of the amplified red-stained epithelial cells from normal breast tissue have missense mutations at evolutionarily conserved amino acids. Jackpot mutations, presumably due to clonal expansion, were common. False-positive missense mutations at conserved residues were observed in 3% of the clear cells (i.e., without red stain), presumably due to DNA polymerase error in early PCR cycles. The allele dropout rate was measured at 40% of the amplified cells. SCIMLA is applicable to a variety of tissues, utilizes a single amplification of an endogenous gene, displays mutant cells in situ, and may be adapted to other species.
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PMID:Single-cell immunohistochemical mutation load assay (SCIMLA) using human paraffin-embedded tissues. 1455 27

DNA polymerase kappa (POLkappa) is a low fidelity translesional DNA polymerase implicated in spontaneous and DNA damage-induced mutagenesis. We have previously shown that POLkappa was frequently overexpressed in human lung cancer tissues as compared with their matched non-tumorous tissue counterpart. In the present study, we found a close correlation between elevated POLkappa expression and p53 inactivation in lung cancer tissues. To investigate whether POLK expression might be regulated by p53, we have determined the transcriptional initiation site of POLK gene and examined its promoter activity in A549, H358-129, and PC-3 human lung cancer cell lines. Wild-type p53, but not a mutant p53 (R273H) devoid of the DNA-binding activity, strongly inhibited POLK promoter activity in these cells. In addition, POLK promoter exhibited a significantly higher activity in p53-/- murine embryo fibroblasts (MEF) than in p53+/- and p53+/+ MEF. These results link p53 status with POLkappa expression and suggest that loss of p53 function may in part contribute to the observed POLkappa upregulation in human lung cancers.
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PMID:Elevated expression of DNA polymerase kappa in human lung cancer is associated with p53 inactivation: Negative regulation of POLK promoter activity by p53. 1520 1

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

Single nucleotide polymorphisms (SNPs) were searched for in 36 genes involved in diverse DNA repair pathways, and 50 nonsynonymous (associated with amino acid changes) SNPs identified were assessed for associations with lung cancer risk by a case-control study consisting of 752 adenocarcinoma cases, 250 squamous cell carcinoma cases and 685 controls. An SNP, Arg72Pro, of the TP53 gene encoding a DNA damage response protein showed the strongest association with squamous cell carcinoma risk (OR Pro/Pro vs. Arg/Arg = 2.2), while 2 other SNPs, Phe257Ser of the REV gene encoding a translesion DNA polymerase and Ile658Val of the LIG4 gene encoding a DNA double-strand break repair protein, also showed associations (OR Ser/Ser vs. Phe/Phe = 2.0 and OR Ile/Val vs. Ile/Ile = 0.4, respectively). An SNP, Thr706Ala, in the POLI gene encoding another translesion DNA polymerase was associated with adenocarcinoma and squamous cell carcinoma risk, particularly in individuals of ages < 61 years (OR Ala/Ala + Ala/Thr vs. Thr/Thr = 1.5 and 2.4, respectively). POLI is the human counterpart of PolI, a strong candidate for the Par2 (pulmonary adenoma resistance 2) gene responsible for adenoma/adenocarcinoma susceptibility in mice. The present results suggest that these 4 SNPs function as genetic factors underlying lung cancer susceptibility by modulating activities to maintain the genome integrity of each individual.
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PMID:Association of amino acid substitution polymorphisms in DNA repair genes TP53, POLI, REV1 and LIG4 with lung cancer risk. 1560 17

Podophyllum hexandrum Royale (Himalayan mayapple), a high-altitude Himalayan plant, has been shown to provide over 80% whole-body radioprotection in mice. To investigate the radioprotective potential of P. hexandrum at the molecular level, expression patterns of various proteins associated with apoptosis were studied in the spleen of male Swiss albino strain A mice by immunoblotting. Treatment with P. hexandrum [200 mg/kg of body weight; an ethanolic 50% (w/v) extract delivered intraperitoneally] 2 h before irradiation resulted in MAPKAP (mitogen-activated protein kinase-activated protein) kinase-2 activation along with HSF-1 (heat-shock transcription factor-1), leading to up-regulation of HSP-70 (heat-shock protein-70) as compared with sham-irradiated (10 Gy) mice. Strong inhibition of AIF (apoptosis-inducing factor) expression was observed in the mice treated with P. hexandrum 2 h before irradiation as compared with the sham-irradiated group. Inhibition in the translocation of free NF-kappaB (nuclear factor kappaB) from cytoplasm to nucleus was observed upon P. hexandrum pretreatment 2 h before irradiation when compared with radiation-treated mice. P. hexandrum pre-treatment (2 h before irradiation) resulted in inhibition of NF-kappaB translocation, and the expression of tumour suppressor protein p53 was observed to be down-regulated as compared with sham-irradiated control. An increase in the expression of proteins responsible for cell proliferation [Bcl-2 (B-cell chronic lymphocytic lymphoma 2), Ras-GAP (Ras-GTPase-activating protein) and PCNA (proliferating cell nuclear antigen)] was observed in the P. hexandrum-pretreated irradiated mice as compared with sham-irradiated controls. Caspase 3 activation resulted PARP [poly(ADP-ribose) DNA polymerase] cleavage, and DNA degradation was strongly inhibited in the mice treated with P. hexandrm (+/-irradiation) as compared with the mice treated with radiation (+/-heat shock). The present study thus clearly demonstrated that P. hexandrum extract provides protection from gamma-radiation by the modulation of expression of proteins associated with cell death.
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PMID:Podophyllum hexandrum (Himalayan mayapple) extract provides radioprotection by modulating the expression of proteins associated with apoptosis. 1576 43

Telomerase is Ribonucleoprotein complex in eukaryocyte, which is composed of telomerase reverse transcriptase(TERT) and telomerase RNA. Telomerase is a special DNA polymerase which can extend the terminal of DNA and maintain the length of telomere. TERT have reverse transcriptase activity. Telomerase activity do not examine in most somatic cell and primary cell, but most tumor cell have strong telomerase activity. It was think that the telomerase has strong relation with tumor occurrences. In this article,the author instruct the correlation of G-strand and P53 in tumor occurrences.
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PMID:[The advance of tumor development mechanism applying mTR-/- mouse model]. 1611 48

Rev3L encodes the catalytic subunit of DNA polymerase zeta (pol zeta) in mammalian cells. In yeast, pol zeta helps cells bypass sites of DNA damage that can block replication enzymes. Targeted disruption of the mouse Rev3L gene causes lethality midway through embryonic gestation, and Rev3L-/- mouse embryonic fibroblasts (MEFs) remain in a quiescent state in culture. This suggests that pol zeta may be necessary for tolerance of endogenous DNA damage during normal cell growth. We report the generation of mitotically active Rev3L-/- MEFs on a p53-/- genetic background. Rev3L null MEFs exhibited striking chromosomal instability, with a large increase in translocation frequency. Many complex genetic aberrations were found only in Rev3L null cells. Rev3L null cells had increased chromosome numbers, most commonly near pentaploid, and double minute chromosomes were frequently found. This chromosomal instability associated with loss of a DNA polymerase activity in mammalian cells is similar to the instability associated with loss of homologous recombination capacity. Rev3L null MEFs were also moderately sensitive to mitomycin C, methyl methanesulfonate, and UV and gamma-radiation, indicating that mammalian pol zeta helps cells tolerate diverse types of DNA damage. The increased occurrence of chromosomal translocations in Rev3L-/- MEFs suggests that loss of Rev3L expression could contribute to genome instability during neoplastic transformation and progression.
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PMID:Loss of DNA polymerase zeta causes chromosomal instability in mammalian cells. 1639 25

DNA polymerase eta (PolH) is the product of the xeroderma pigmentosum variant (XPV) gene and a well-characterized Y-family DNA polymerase for translesion synthesis. Cells derived from XPV patients are unable to faithfully bypass UV photoproducts and DNA adducts and thus acquire genetic mutations. Here, we found that PolH can be up-regulated by DNA breaks induced by ionizing radiation or chemotherapeutic agents, and knockdown of PolH gives cells resistance to apoptosis induced by DNA breaks in multiple cell lines and cell types in a p53-dependent manner. To explore the underlying mechanism, we examined p53 activation upon DNA breaks and found that p53 activation is impaired in PolH knockdown cells and PolH-null primary fibroblasts. Importantly, reconstitution of PolH into PolH knockdown cells restores p53 activation. Moreover, we provide evidence that, upon DNA breaks, PolH is partially colocalized with phosphorylated ATM at gamma-H2AX foci and knockdown of PolH impairs ATM to phosphorylate Chk2 and p53. However, upon DNA damage by UV, PolH knockdown cells exhibit two opposing temporal responses: at the early stage, knockdown of PolH suppresses p53 activation and gives cells resistance to UV-induced apoptosis in a p53-dependent manner; at the late stage, knockdown of PolH suppresses DNA repair, leading to sustained activation of p53 and increased susceptibility to apoptosis in both a p53-dependent and a p53-independent manner. Taken together, we found that PolH has a novel role in the DNA damage checkpoint and that a p53 target can modulate the DNA damage response and subsequently regulate p53 activation.
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PMID:DNA polymerase eta, the product of the xeroderma pigmentosum variant gene and a target of p53, modulates the DNA damage checkpoint and p53 activation. 1644 51

The tumor suppressor p53 plays a central role in the DNA damage response. p53 enhances base excision repair (BER), in part, through direct interaction with the repair complex. Mitochondrial DNA (mtDNA) is repaired by a mtBER pathway. Many colorectal cancers harbor mtDNA mutations that are associated with poor prognosis. In addition to modulating the apoptotic response, mitochondria-localized p53 also stimulates mtBER. However, the mechanisms by which p53 enhances colorectal cancer mtBER after stress remain unclear. To explore this, we used colorectal cancer cells isogenic for p53 (HCT116p53+/+ and HCT116p53-/-). p53+/+ cells more efficiently repaired H(2)O(2) damaged DNA in vivo as measured by semiquantitative mtDNA displacement loop PCR. Mitochondrial extracts from p53+/+ cells more efficiently stimulated (32)P-dCTP incorporation into a uracil-oligonucleotide. Recombinant p53 complemented p53-/- mitochondrial extract repair of uracil or 8-oxo-G-containing oligonucleotides. As a measure of DNA glycosylase activity, p53+/+ mitochondrial extracts more efficiently incised uracil or 8-oxo-G oligonucleotides, although recombinant p53 could not stimulate oligonucleotide incision. p53 did not influence mitochondrial apurinic/apyrimidinic endonuclease activity measured by incision of a tetrahydrofuran-oligonucleotide. p53+/+ mitochondrial extracts had higher DNA polymerase-gamma activity measured by (32)P-dCTP incorporation into a single-nucleotide gap oligonucleotide, and recombinant p53 complemented p53-/- mitochondrial extract DNA polymerase-gamma activity. mtDNA ligase activity was not affected by p53 status. p53 protein was detected in an inner mitochondrial membrane subfraction containing components of the mtBER complex. Our data suggest that an intact p53 pathway stimulates specific mtBER steps and provides mechanistic insight into the development of mtDNA mutations in colorectal cancer.
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PMID:The p53 pathway promotes efficient mitochondrial DNA base excision repair in colorectal cancer cells. 1658 72


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