Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q9UIJ5 (Rec)
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The tracheal mucosa of the Syrian golden hamster has been extensively employed as a model system for respiratory tract cell renewal, injury, and carcinogenesis. However, baseline cell kinetic data are not available for normal juvenile and adolescent animals in which the mucosa and cartilage are rapidly enlarging. The objective of this research was to elucidate alterations in cell kinetics, epithelial morphology, and gene expression in the trachea of hamsters at different ages. Cell kinetics were examined by 3H-thymidine labeling indices, morphology by light and electron microscopic examination, and gene expression by slot blot analysis. Results showed that mucosal epithelium of the young and adolescent hamster undergoes cyclic necrosis and cell shedding, exposing portions of the elastic basal lamina. Epithelial shedding was associated with hyperplasia and squamous metaplasia. Additionally, the labeling indices of mucosal epithelial cells and chondroblasts also exhibited variable patterns which were associated with a cyclic pattern of expression of c-fos and c-erbB2 proto-oncogenes and epidermal growth factor receptor.
Anat Rec 1992 Jun
PMID:Cell renewal and gene expression in the trachea of hamster at different ages. 160 90

Mutagenesis, clastogenesis, and carcinogenesis, may all be S-phase dependent processes within carcinogen-damaged human cells. Carcinogens have been shown to inhibit replicative DNA synthesis in S phase cells and the mechanisms of inhibition have been identified. It is proposed that the sequelae of carcinogen action (mutations, sister-chromatid exchanges, chromosome aberrations) are the consequence of the production of lesions in the DNA template which interfere with the ability of DNA polymerase to synthesize a complementary strand without error. Mis-instructive lesions in the template give rise to base-substitution mutations in nascent strands as DNA polymerase inserts an incorrect but complementary base. Non-instructive base lesions and sterically interfering bulky adducts in the template inhibit DNA polymerase and cause the growing points of nascent DNA strands to be blocked. This blockage perpetuates discontinuities in daughter strands. These discontinuities are eliminated by a process known as post-replication repair. Blocked growing points may be relieved by un-directed insertion of DNA precursors to span the non-instructive lesions. Transient dislocation of the primer terminus from the damaged template may occur at palindromic or repetitive sequences. Reannealing of the primer terminus beyond the site of damage may allow bypass of blocking lesions with a consequence of deletion or insertion of genetic information. DNA at the site of blocked growing points may be a substrate for other enzymes involved in DNA metabolism. Single-strand gaps in daughter strands may be recognized by Rec A-like proteins which catalyze paranemic invasion of sister duplex strands. Recombination intermediates generated at sites of blocked growing points may be resolved by a pathway that produces either sister-chromatid exchanges or the insertion of a patch of parental template DNA within the daughter strand. Single-strand-specific endonuclease may attack regions of denatured DNA at blocked growing points producing double-strand breaks which appear to be intermediates in the formation of chromatid aberrations. The utilization of each of these pathways of post-replication repair will depend upon the precise structure of the template lesion, the sequence context in which the lesion is embedded in the template strand, and stochastic processes.
Carcinogenesis 1989 Jan
PMID:Pathways of human cell post-replication repair. 264 48

5-Nitro-2-furylacrylic acid (5-NFA) caused dose dependent inhibition of growth of Escherichia coli K-12 strain AB 2480 (uvr-, rec-), the 37% (D37) and 10% (D10) survival doses being 1.0 microgram/ml.h and 1.75 micrograms/ml.h, respectively. Although much higher doses of drug were required to achieve comparable inhibition of growth of E. coli strain 1157 (repair proficient), significant filamentation of these cells was produced by treatment with 1.0 microgram/ml 5-NFA for 4 hr. Ultraviolet absorption data and thermal chromatography through hydroxyapatite (HAP) column revealed that 5-NFA treatment of E. coli strain AB 2480 produced more than 80% of DNA reversibly bihelical due to the formation of interstrand cross-links and the initial part of the reaction obeyed a first order relation. 5-NFA also produced dose-dependent increase of prophage induction in E. coli strain GY 5027: envA, uvrB, ampA1, strA (lambda). The implications of the action of 5-NFA on DNA in relation to the induction of 'SOS' functions and carcinogenesis were discussed.
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PMID:DNA damage by 5-nitro-2-furylacrylic acid, a nitrofuran derivative. 331 11

The data on mouse skin thickness reported here was prompted by the need to know the true position of basal cells of the epidermis and hair follicles as these are important "cells at risk" for a variety of skin reactions including carcinogenesis following exposure to radiation. There is little reliable data in the literature and most previous reports have ignored the shrinkage of skin that occurs because of its natural elasticity. The values determined for mouse flank skin in telogen--the resting phase of the hair cycle for the different skin layers--are epidermis 10 micron, corium 250 micron, adipose layer 150 micron, and hair follicle depth 150 micron. Three days after chemical depilation which triggers the hair follicles into active cycle (anagen) the epidermis doubles in thickness, remains at this value for 7 days, and then gradually returns to telogen values by day 18. The corium and adipose layers also increase significantly to reach approximately 390 micron and approximately 260 micron, respectively, by day 10 and then return to control values from day 15 onward. The change in hair follicles depths are more dramatic with active follicle basal cells reaching approximately 450-550 micron into the adipose layer between days 7 and 15. One important finding is that chemical depilation does not affect the telogen thickness of skin-the teleogen values for the epidermis and dermis immediately prior to and immediately after depilation were similar to those 23 days later at the beginning of the next telogen phase.
Anat Rec 1984 Dec
PMID:The influence of the hair cycle on the thickness of mouse skin. 652 97

4-(N-Butylnitrosamino)-4-hydroxybutyric acid lactone (BBAL) was synthesized as a possible intermediate produced by metabolic activation of a selective bladder carcinogen, N-butyl-N-(3-carboxypropyl)nitrosamine. BBAL was stable in neutral sodium phosphate buffer (ionic strength, 0.2), having a half-life of more than 30 hr at 25 degrees. The mutagenic effects of BBAL were tested with the use of Salmonella typhimurium TA1535 and Escherichia coli B/rWP2-try-, WP2-try-hcr-, and Sd4. The gene-damaging effects were assayed by repair tests with Bacillus subtilis H17 (rec+) and M45 (rec-). BBAL showed potent effects in the mutation and repair tests on all the strains tested without activation. A possibility is suggested for the metabolic activation of N-butyl-N-(3-carboxypropyl)nitrosamine to BBAL by alpha-hydroxylation at the site of the 3-carboxypropyl chain followed by lactonization in target tissues prior to interaction with macromolecules to lead to carcinogenesis.
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PMID:Synthesis and mutagenicity of 4-(N-butylnitrosamino)-4-hydroxybutyric acid lactone, a possible activated metabolite of the proximate bladder carcinogen N-butyl-N-(3-carboxypropyl)nitrosamine. 676 16

Dinitrosocimetidine and mononitrosocimetidine were tested in a series of short term assay systems. Both compounds were mutagenic in the absence of rat liver microsomes. The dinitrosocimetidine produced higher mutagenic or clastogenic effects at concentrations that were 50 to 500 times lower than the concentrations at which the mononitrosocimetidine produces its maximum effects. The most sensitive short term assay system was the Chinese hamster ovary cell culture system. Dinitrosocimetidine caused sister chromatid exchanges at a concentration of 10(-8) M and chromosome aberrations at 10(-7) M in this system. Dinitrosocimetidine had moderate activity in the bacterial short term assay systems. In the Ames test, strain TA 100 was the most sensitive. The compound was of lower activity in the E. coli WP-2 and the E. coli rec- systems.
Carcinogenesis 1981
PMID:Mutagenicity of nitrosated cimetidines. 702 25

The role of DNA repair genes (uvrA, uvrB, uvrD, recA, recB, lexA, and umuC) in spontaneous mutation rate per bacterium per cell division (micro) was determined for the reversion of UAA (his-4 and trpE65), UAG (lacZ53), and frameshift (trpE9777) mutations, and for the occurrence of forward mutations to valine resistance. Rich growth medium enhanced micro in a wildtype strain but not in a uvrB5 strain. In minimal growth medium, the uvrA and uvrB strains had the largest micro (1.9-6.2-fold greater than that for isogenic wild-type strains, depending on the mutation assay). The uvrB strains carrying lexA, recA, umuC, or both the uvrD and rec B mutations (in combination), i.e., mutations that inhibit error-prone DNA repair, had the lowest micro values (approximately 10-fold less than the uvrB strain). Teh recA and lexA mutations also reduced micro (by approximately 2-fold) in uvr+ strains. The genetic control of the error prone repair-dependent sector of spontaneous mutagenesis was shown to be qualitatively similar to the genetic control for u.v. radiation mutagenesis. The umuC mutation, which drastically reduced spontaneous mutagensis, had no effect on genetic recombination. It is proposed that the low level of spontaneous mutagenesis observed in the recA, lexA, umuC, and the uvrD recB strains is due to errors made during DNA replication, while the enhanced level of spontaneous mutagenesis observed in the wild type, and especially in the uvrA and uvrB strains, is due to excisable lesions that are produced in the DNA by normal metabolic reactions, and that such unexcised lesions induce mutations via error-prone DNA repair. These results are discussed in terms of their relevance to spontaneous carcinogenesis.
Carcinogenesis 1981
PMID:Much of spontaneous mutagenesis in Escherichia coli is due to error-prone DNA repair: implications for spontaneous carcinogenesis. 702 9

1,2-dimethylhydrazine (DMH), administered weekly to mice for 20 weeks, induces tumors in the distal segment of colon. Tumors are preceded by enlargement of the mucosal glands resulting from increases in the number of total cells and 3H-thymidine labeled cells/crypt. Cells located in the crypt base normally undergo 2-3 division as they migrate toward the lumen, and they become post-mitotic in the upper crypt. It is not known if cells in these enlarged crypts have rates of turnover similar to cells in normal crypts. Groups of w/s female mice were treated with DMH (20 mg/kg body wt) for 3,8, or 16 weeks; controls were given 0.001 M EDTA. After treatment, the animals were injected with 3H-thymidine and killed one hour or 1,2,4,7 or 17 days later. Autoradiographs were prepared from sections of distal colon. The total cells/crypt column in 30 crypts/animals were counted. Crypts were divided into 10 equal segments based on the crypt length and the labeled cells/segment were counted. The relative number of labeled cells and the distribution of these cells within crypts were similar in DMH-treated and control animals after one hour. However, as the cells migrated toward the lumen, the number of labeled cells doubled after 2 days and tripled after 4 days in DMH-treated animals but only doubled during the 4 days in controls. This difference caused by retention of an increased number of dividing cells in the lower 4 segments of the crypts and suggests an increase in those cells that divide twice. In addition, increased numbers of labeled cells were retained in the upper 3 segments of DMH-treated animals after 4 days. These findings indicate that the crypt cells of DMH-treated animals are generally more immature than those of controls and this immaturity contributes to the enlargement of mucosal glands during carcinogenesis.
Anat Rec 1981 Jul
PMID:The effect of the carcinogen, 1,2-dimethylhydrazine, on turnover of 3H-thymidine labeled cells from mucosal glands of mouse colon. 727 Sep 30

Breast cancer is one of the most common malignancies among women. The molecular mechanisms involved in breast carcinogenesis, however, remain to be elucidated. Although somatic mutation of BRCA1 is rare, BRCA1 protein expression is reduced in about 30% of sporadic breast carcinomas (Yoshikawa et al., Clin. Cancer Res., 5:1249-1261, 1999), indicating its possible involvement even in sporadic breast carcinogenesis. Among the BRCA1-interactive proteins are hRAD51 (a human homologue of Escherichia coli rec A protein), BARD1 (BRCA1-associated RING domain 1) and p53, all of which are involved in DNA repair. We have analyzed the expression patterns of the hRAD51, BARD1 and p53 proteins in five breast cancer cell lines, including a BRCA1-deficient cell line, and in 179 breast cancer tissue samples from Japanese women, including 113 sporadic, 47 hereditary (i.e., BRCA1 status unknown), and 19 BRCA1-associated cases. Of the 179 breast carcinomas, fifty-four (30%) exhibited reduced hRAD51 expression, and sixty-two (35%) exhibited p53 overexpression. On the other hand, reduced expression level of BARD1, and of hMSH2 and hMLH1, which are components of DNA mismatch-repair pathway and are involved in colorectal carcinogenesis, was observed respectively in only 10 (6%), 8 (5%) and 3 (2%) cases. The overall frequency of sporadic breast carcinomas with abnormal expression of either BRCA1 or the BRCA1-interactive proteins was 67% (76/113). These results indicate that there may be an important role for the BRCA1-associated DNA-repair pathway, not only in BRCA1-associated breast carcinomas, but also in sporadic breast carcinomas.
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PMID:Abnormal expression of BRCA1 and BRCA1-interactive DNA-repair proteins in breast carcinomas. 1096 36

Bloom syndrome (BS) displays one of the strongest known correlations between chromosomal instability and an increased risk of malignancy at an early age. The prevention of genomic instability and cancer depends on a complex network of pathways induced in response to DNA damage and stalled replication forks, including cell-cycle checkpoints, DNA repair, and apoptosis. Several studies have demonstrated that BLM is involved in the cellular response to DNA damage and stalled replication forks. BLM interacts physically and functionally with several proteins involved in the maintenance of genome integrity and BLM is redistributed and/or phosphorylated in response to several genotoxic stresses. The data concerning the relationship between BLM and these cellular pathways are summarized and the role of BLM in the rescue of arrested replication forks is discussed. Moreover, I speculate that BLM deficiency is lethal, and that BLM-deficient cells escaping apoptotic death do so by constitutively inducing a bacterial SOS-like response including the induction of alternative replication pathway(s) dependent on recombination, contributing to the mutator and hyper-Rec phenotypes characteristic of BS cells. This mechanism may be dependent on the RAD51 gene family, and involved in carcinogenesis in the general population.
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PMID:Bloom syndrome, genomic instability and cancer: the SOS-like hypothesis. 1595 Mar 75


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