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 distribution of proliferating cells was studied in colorectal carcinoma by immunohistochemistry using monoclonal antibody-DNA polymerase alpha and Ki-67. Colorectal carcinoma was classified into two types by growth mode: (1) intramucosal polypoid growth carcinoma and (2) non-polypoid growth carcinoma. The labeling index of anti-DNA polymerase alpha and Ki-67 in non-polypoid growth carcinoma was significantly higher than in polypoid growth carcinoma. The labeling index of polypoid growth carcinoma was significantly higher than adenoma. The proliferating cells in polypoid growth carcinoma and adenoma were mainly distributed in the upper third of intramucosal neoplastic gland. However, in non-polypoid growth carcinoma, the proliferating cells of intramucosal lesion were scattered mainly in the lower third along the neoplastic gland. The distribution pattern of proliferating cells in early carcinoma with non-polypoid growth were similar to those of non-polypoid growth advanced carcinoma. These results suggested that submucosal invasion occurred more rapidly in intramucosal non-polypoid growth carcinoma.
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PMID:[Immunohistochemical study of proliferative cells in colorectal adenoma and carcinoma]. 146 Jul 66

Cell renewal in the large intestine mucosa is normally tied to a rigidly compartmentalized model. Immunohistochemical identification of cells in S phase through uptake of bromodeoxyuridine is the method of choice for detailed compartmental mapping of proliferation, while immunohistochemical detection of proliferation-associated antigens (Ki-67, PCNA, DNA polymerase alpha) provides information in advanced tumor cases. Mucosal hyperproliferation due to inflammation may be transient (self-limited colitis, Crohn's disease, acute radiation damage) or lasting (ulcerative colitis). Progressive shifting of the proliferation zone to the crypt surface (Stage II abnormality) is a late feature of irradiated rectal mucosa and subgroups of ulcerative colitis patients at high risk for cancer. Hyperproliferation and Stage II abnormality coexist in the mucosa of patients with colorectal neoplasia, but are mutually independent and correlated to different clinical and pathological features of the disease. These cytokinetic abnormalities are highly predictive markers of the adenoma-carcinoma sequence, but are not associated with de novo adenocarcinoma. Proliferation increases progressively in the subsequent steps of this sequence, except in early cancer.
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PMID:Cell proliferation in colorectal tumor progression: an immunohistochemical approach to intermediate biomarkers. 146 8

DNA polymerase alpha is an endogenous DNA replication enzyme expressed in all cells in a proliferation cycle. An immunoperoxidase method and the monoclonal antibody to DNA polymerase alpha were used to identify proliferating cells in colorectal carcinomas (n = 35) and adenomas (n = 43). The labeling index (L.I.) in colorectal carcinomas was 51.6%, being significantly higher than 28.6% in adenomas. The L.I. in colorectal carcinomas correlated with clinical staging (stage I: 33.1%, stage II and III: 49.5%, stage IV and V: 66.9%). Furthermore, the L.I. had a tendency to elevate as carcinoma deeply invaded (pm: 25.8%, ss-s or a1-a2: 52.2%, si or ai: 67.5%). The L.I. in adenoma was related to the degree of atypia. The L.I. in adenomas with mild atypia, with moderate atypia, and cancer in adenoma were 18.3%, 31.5%, and 47.0%, respectively. And the L.I. of cancer in adenoma had no significant difference in advanced carcinomas (47.0% vs 51.6%). These results suggest that the L.I. is useful as a marker for evaluating the degree of biological malignancy of human colorectal carcinomas and the degree of histopathological atypia of adenomas.
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PMID:[Detection of proliferative cells in colorectal carcinomas and adenomas by monoclonal antibody to DNA polymerase alpha]. 227 35

We have successfully established one murine hybridoma that secretes a monoclonal antibody specific for the 77,000 subunit of human DNA polymerase alpha. The results of immunochemical studies, using HDR-854-E4 monoclonal antibody (MAb) and immunoperoxidase detection methods, demonstrate intranuclear and intracytoplasmic localisation of the subunit in all the human culture cell lines tested. The immunoperoxidase reaction product exhibits a diffuse pattern of distribution within the cytoplasm and nucleoplasm, but nucleoli are clearly negative. In cultured cell lines, HeLa and KATO III, more than 95% of the cells are positive, suggesting that the subunit antigens persist throughout the mitotic cycle. No subunit antigen was recognised in resting mononuclear cells (MNC). Immuno-electron microscopic examination of HeLa cells confirms and extends these observations. We have further examined the expression level of the subunit antigen in various normal and cancerous tissues. Strong reaction was observed in proliferating normal and cancer cells such as cancer cells from the gastrointestinal (GI) tract, thyroid, malignant lymphoma, breast, cells in the germinal centres of lymph nodes, epithelial cells in the GI tract and nephrogenic zones in fetal kidney. Finally, we utilised this antibody as a diagnostic tool in biopsies of the thyroid and GI tract. Thyroid cancer was stained positively with this antibody, while follicular adenoma was not. Gastric cancer was stained strongly and adenomatous polyp and hyperplastic polyp were stained moderately. This antibody is not only specific and powerful for application of a novel approach to the complex biochemical mechanisms of mammalian DNA replication, but also useful for distinction between proliferative and non-proliferative lesions.
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PMID:Intracellular localisation of a subunit of human DNA polymerase alpha affecting primase activity recognised by monoclonal antibody (HDR-854-E4) and its application to distinction between proliferative and non-proliferative lesions. 276 63

The recurrence rate of pituitary adenomas has been reported to be as high as 10% to 35% despite their generally benign nature. A monoclonal antibody directed against proliferating cell nuclear antigen (PCNA) was used to investigate whether the proliferative index might help to predict adenoma recurrence. This antigen is a nuclear protein identified as the auxiliary protein of deoxyribonucleic acid polymerase delta, and its gene expression correlates with cell proliferation. The authors studied 30 patients with recurrent pituitary adenomas, 32 with nonrecurrent adenomas, and seven normal pituitary tissue samples. The mean interval to recurrence ( +/- standard error of the mean) was 5.3 +/- 0.7 years. The age- and sex-matched nonrecurrent group had a mean follow-up period of 6.6 +/- 0.3 years without clinical recurrence. Mean percentages of PCNA-positive tumor nuclei in both the initial and the second surgical specimens of the recurrent adenomas (13.45% +/- 3.02% and 19.56% +/- 3.66%, respectively) were significantly higher than that of the nonrecurrent group (2.49% +/- 1.21%). In addition, recurrent tumors had a higher PCNA index than the initial tumors in the same patients. Normal anterior pituitary gland tissue had a significantly lower mean PCNA index (0.12% +/- 0.11%) than either patient group. Stepwise multivariate regression analysis indicated that factors which collectively correlated significantly with recurrence were: high PCNA index, large tumor size, extrasellar extension, and incomplete surgical excision. The PCNA nuclear count was not associated with age, sex, or hormone hypersecretion, but was higher in macro- than in microadenomas, in tumors with extrasellar extension, and in those incompletely excised. A higher PCNA index also correlated with a shorter disease-free interval. The authors conclude that evaluation of the PCNA index assists in predicting the likelihood of pituitary adenoma recurrence.
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PMID:Significance of proliferating cell nuclear antigen index in predicting pituitary adenoma recurrence. 809 73

Immunohistochemical detection of the nuclear antigen recognised by the monoclonal antibody Ki67, DNA polymerase alpha, and the proliferating cell nuclear antigen (PCNA), and histochemical staining for the argyrophilic proteins associated with the nucleolar organizer regions (AgNOR) were carried out on histological sections from 107 colorectal adenomas containing invasive carcinoma (ACIC), including 7 with regional lymph node metastases. Separate evaluations were made for fields corresponding to adenoma with low-grade dysplasia, adenoma with high-grade dysplasia and early cancer. The same techniques were also employed in 20 cases of normal mucosa and 20 advanced carcinomas. The mean percentages of Ki67, DNA polymerase alpha, and PCNA-positive nuclei and the number of AgNOR per nucleus progressively increased along the sequence from normal mucosa via low-grade and high-grade dysplasia adenoma to advanced cancer, whereas the early cancer values were not significantly different from those in the low-grade dysplasia areas. No significant difference in PCNA positivity and number of AgNOR were noted in ACIC with and without lymph node metastases. It is suggested that the decrease in proliferative activity thus revealed in early cancer may be due to changes in the submucosa microenvironment caused by invasion, and that the metastatic potential of an early colorectal cancer cannot be correlated to such activity.
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PMID:Cell proliferation in colorectal adenomas containing invasive carcinoma. 809 91

We studied cell kinetics of colo-rectal neoplasms using PCNA (the auxiliary protein of DNA polymerase-delta) immunohistochemistry. We analyzed the distribution pattern of PCNA positive cells on normal colon mucosa, adenoma (6 cases) and cancer (early: 33 cases, advanced: 6 cases). PCNA positive index (PI) was calculated as the percentage of PCNA positive tumor cells in relation to the total number (about 1000) of the tumor cells. PCNA positive indices were 30% in normal colon mucosa, 49% in adenoma and 72% in cancer, respectively. There were statistically significant differences between three mean values (p < 0.01). In normal colon mucosa PCNA positive cells are localized at the lower part of mucosa, but, in adenoma, they are found at the more upper part of mucosa too. In cancer, PCNA positive cells were localized diffusely and their immunoreactivity is higher than those of the normal mucosa and adenoma. In conclusion, our results suggests that the ratio of PCNA positive cells almost equivalents to growth fraction, and is correlated with the histological grading of colo-rectal tumor, but not correlated with depth of carcinoma. It is presumed that carcinoma has a higher ratio of PCNA positive cells than adenoma, and therefore carcinoma has higher proliferating cell density than adenoma.
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PMID:[A study of changes in distribution pattern of proliferating cells associated with progression of human colorectal benign and malignant tumor using PCNA immunohistochemistry]. 809 82

The Pulmonary adenoma resistance 2 (Par2) locus of the BALB/cByJ mouse, located within 0.5 cM of chromosome 18, is responsible for reducing the mean multiplicity of urethane-induced lung tumors relative to those in C57BL/6J, A/J and C3H/HeJ mice. Thus, BALB/B6-Par2 congenic strain genetically identical to BALB/cByJ except carrying C57BL/6J Par2 alleles develops seven times more tumors than BALB/cByJ. To gain clues for identification of Par2 candidate genes, we analysed lung tumorigenesis in BALB/cByJ<-->BALB.B6-Par2 chimeric animals. Of 100 tumors induced by urethane in 16 chimeras, 82 originated from BALB.B6-Par2 cells, indicating the Par2 phenotype to be cell-autonomous. In addition, the BALB.B6-Par2- and BALB/cByJ-derived tumors were similar in mean size, implying that the phenotype is primarily expressed during initiation rather than in the promotion stage of carcinogenesis. Given these results, we surveyed a comprehensive mouse genome database and physically mapped Par2 within a 2.3 Mbp segment containing three known genes, Poli, Mbd2 and Dcc. Among those, the Poli seemed to be the most reasonable Par2 candidate, since it encodes an extremely error-prone DNA polymerase preferentially incorporating G or T opposite template T in vitro, reminiscent of the Kras2 activation because of an A to G or T point mutation within codon 61 with which most urethane-induced lung tumors are initiated. Indeed, our sequencing of Poli cDNAs from BALB/cByJ, C57BL/6J, A/J and C3H/HeJ lungs revealed 21 BALB/cByJ-specific single-nucleotide polymorphisms in the coding region accompanied by seven amino-acid substitutions and an elevated frequency of alternative splicing, while no polymorphisms associated with tumor susceptibility were found for either Mbd2 or Dcc. Notably, we obtained evidence that BALB/cByJ Par2 alleles may selectively decrease the frequency of Kras2-mutated tumors compared with C57BL/6J alleles. Consequently, the Poli is an intriguing Par2 candidate clearly deserving further evaluation.
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PMID:Analysis of lung tumorigenesis in chimeric mice indicates the Pulmonary adenoma resistance 2 (Par2) locus to operate in the tumor-initiation stage in a cell-autonomous manner: detection of polymorphisms in the Poli gene as a candidate for Par2. 1270 Jun 72

In this study, we performed systematic candidate gene analyses of the Pulmonary adenoma resistance 2 locus. Differential gene expression in lung tissues and nucleotide polymorphisms in coding regions between A/J and BALB/cJ mice were examined using reverse transcription-PCR and direct sequencing. Although not all genes in the interval were analyzed at this moment due to the recent database updating, we have found that the Pol iota gene, encoding the DNA polymerase iota, contains 25 nucleotide polymorphisms in its coding region between A/J and BALB/cJ mice, resulting in a total of ten amino acid changes. Primer extension assays with purified BALB/cJ and A/J proteins in vitro demonstrate that both forms of Pol iota are active but that they may differ in substrate discrimination, which may affect the formation of Kras2 mutations in mouse lung tumors. Altered expression of POL iota protein and an amino acid-changing nucleotide polymorphism were observed in human lung cancer cells, suggesting a possible role in the development of lung cancer. Thus, our data support the Pol iota gene as a modifier of lung tumorigenesis by altering DNA polymerase activity.
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PMID:Pol iota is a candidate for the mouse pulmonary adenoma resistance 2 locus, a major modifier of chemically induced lung neoplasia. 1502 25

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


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