UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trichothiodystrophy (TTD) is a rare genetic disease with heterogeneous clinical features associated with specific deficiencies in nucleotide excision repair. Patients have brittle hair due to a reduced content of cysteine-rich matrix proteins. About 50% of the cases reported in the literature are photosensitive. In these patients an altered cellular response to UV, due to a specific deficiency in nucleotide excision repair, has been observed. The majority of repair-defective TTD patients have been assigned by complementation analysis to group D of xeroderma pigmentosum (XP). Recently, the human excision repair gene ERCC2 has been shown to correct the UV sensitivity of XP-D fibroblasts. In this work we describe the effect of ERCC2 on the DNA repair deficient phenotype of XP-D and on two repair-defective TTD cell strains (TTD1VI and TTD2VI) assigned by complementation analysis to group D of XP. ERCC2 cDNA, cloned into a mammalian expression vector, was introduced into TTD and XP fibroblasts via DNA-mediated transfection or microneedle injection. UV sensitivity and cellular DNA repair properties, including unscheduled DNA synthesis and reactivation of a UV-irradiated plasmid containing the chloramphenicol acetyltransferase reporter gene (pRSVCat), were corrected to wild-type levels in both TTD and XP-D cells. These data show that a functional ERCC2 gene is sufficient to reestablish a wild-type DNA repair phenotype in TTD1VI and TTD2VI cells, confirming the genetic relationship between TTD and XP-D. Furthermore, our findings suggest that mutations at the ERCC2 locus are responsible for causing a similar phenotype in TTD and XP-D cells in response to UV irradiation, but produce quite different clinical symptoms.
Carcinogenesis 1994 Aug
PMID:Correction by the ERCC2 gene of UV sensitivity and repair deficiency phenotype in a subset of trichothiodystrophy cells. 805 25

Nucleotide-excision repair (NER) is an important cellular defence mechanism against mutagenesis and carcinogenesis. The essential yeast genes RAD3 (ref. 2) and SSL2 (RAD25), homologues of the human xeroderma pigmentosum genes XPD and XPB respectively, have been implicated in NER in yeast. The products of these genes are also subunits of (Rad3 protein) or associate with (Ssl2 protein) purified yeast RNA polymerase II transcription initiation factor b, the counterpart of human TFIIH. Rad3 and Ssl2 proteins may participate directly in NER. Alternatively, they may function exclusively as transcription factors that support NER by influencing the expression of other NER genes. Here we show that defective NER in rad3 mutant extracts can be specifically complemented by purified transcription factor b. Similarly, defective NER in ssl2 mutant extracts is corrected by purified factor b/Ssl2 complex. These results support a direct role of factor b during NER in yeast. Hence, factor b (TFIIH) has a dual role in transcription and NER.
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PMID:Transcription factor b (TFIIH) is required during nucleotide-excision repair in yeast. 810 88

Xeroderma pigmentosum is a group of rare autosomal recessive disorders with defective DNA repair that provide insight into the basic mechanism of carcinogenesis. It is the best human model linking clinical abnormalities and neoplasia to carcinogen exposure. We describe a patient with xeroderma pigmentosum and numerous basal cell carcinomas, squamous cell carcinomas, and melanomas treated with radiation therapy, Mohs micrographic surgery, dermabrasion, and isotretinoin prophylaxis.
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PMID:Management of a young patient with xeroderma pigmentosum. 817 Aug 56

The effect of UV photoproducts or benzo[a]pyrene-diol-epoxide-I (BPDE-I) adducts in DNA on the transient expression of a reporter gene was measured in mammalian cells. The plasmid pRSVCAT was UV irradiated or treated with BPDE-I in vitro and co-transfected with undamaged pRSVBGAL into mouse and human fibroblasts. Variations in transfection efficiency among different cell lines were corrected by adjusting the volumes of cell extracts used in the chloramphenicol acetyl transferase (CAT) assays to contain equal beta-galactosidase (BGAL) activity. The expression of the CAT gene was found to decrease exponentially after transfection of pRSVCAT containing increasing numbers of DNA lesions per molecule. The average number of BPDE-I adducts per plasmid molecule was measured by ELISA; the average number of pyrimidine dimers was estimated from the dose kinetics for the disappearance of the supercoiled form of irradiated plasmid DNA treated with Micrococcus luteus UV endonuclease. By expressing the inhibition of CAT activity in terms of the average number of lesions per gene, we were able to compare directly the effects of two different carcinogen lesions on transient transcription. We observed comparable kinetics of inhibition of gene expression by BPDE-I adducts and pyrimidine dimers in DNA. D0 values determined by linear regression analysis of dose-response curves for inhibition of CAT activity were 4.9 BPDE-I adducts or 6.6 pyrimidine dimers per gene in excision-proficient human fibroblasts; the corresponding values in mouse cells were 4.4 BPDE-I adducts or 5.5 pyrimidine dimers. Similar threshold densities of BPDE-I adducts and pyrimidine dimers were observed before inhibition of transcription from pRSVCAT was detected. No threshold was observed in experiments with human fibroblasts deficient in excision repair (xeroderma pigmentosum group A); calculated D0 values were 1.2 pyrimidine dimers of 2.1 BPDE-I adducts. Our results permit direct comparisons of the magnitude of inhibition of gene transcription by distinct DNA lesions, and suggest that BPDE-I adducts and UV-induced cyclobutane pyrimidine dimers in template DNA block transcription with similar efficacy.
Carcinogenesis 1994 May
PMID:Inhibition of reporter gene expression in mammalian cells. Effects of distinct carcinogen lesions in DNA. 820 75

It has become evident that retinoids control differentiation, embryonal development, and tumorigenesis. In animal models, skin tumorigenesis has been shown to be prevented by retinoids, which in this organ function as antitumor promoters in the two-stage system using 7,12-dimethylbenz(a)anthracene (DMBA) as the initiator, and 12-tetradecanoyl-phorbol-13-acetate (TPA) as tumor promoter. Even though pharmacological doses applied topically appear to inhibit tumor formation, we found that papilloma and keratoacanthoma growth required physiological concentrations of retinoic acid and that vitamin A deficiency was even more effective than excess retinoid in inhibiting SENCAR mouse skin tumorigenesis. In human beings, oral administration of retinoic acid after tumor resection was effective in inhibiting the appearance of new tumors on the skin of four patients with Xeroderma Pigmentosum, and was effective in preventing new primary tumor formations in patients treated for head and neck cancer. The newly-discovered nuclear receptors for retinoic acid function as transcriptional activators for several genes. In patients with acute promyelocytic leukemia presenting with a reciprocal translocation of chromosome 17 to chromosome 15, the breakpoint has been identified in the retinoic acid receptor alpha gene, which forms a fusion gene with a new gene termed myl, on chromosome 15. Treatment of the patients with retinoic acid causes complete remission of the APL. It also appears to generate cells that do not bear the translocation. Therefore, retinoids may well function as modulators of carcinogenesis both at the promotion level as well as by causing differentiation of neoplastically transformed cells.
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PMID:Multiple mechanisms: the example of vitamin A. 830 28

Cytochromes P450 catalyze the bioactivation of many carcinogens. In particular, cytochrome P450 1A1 (CYP1A1) catalyzes the conversion of polycyclic aromatic hydrocarbons, such as benzo[a]pyrene, into potent mutagenic agents. Human skin fibroblasts, both DNA repair deficient (xeroderma pigmentosum group A: XPA) and DNA repair normal have been co-transformed with a chimeric gene construct containing human CYP1A1 coding sequences controlled by the cadmium (Cd) ion inducible mouse metallothionein-I promoter and pRSV-NEO, a dominant selectable marker for G418 resistance. Individual G418 resistant colonies were cloned and analyzed for Cd inducible CYP1A1 activity. Six clones of DNA repair deficient cells and five clones of DNA repair proficient cells have been isolated which express Cd inducible CYP1A1. Benzo[a]pyrene-trans-7,8-diol (BPD) is cytotoxic in Cd induced CYP1A1 expressing cells. The cytotoxicity can be inhibited by 10 microM alpha-napthoflavone. Differential cytotoxicity between the DNA repair deficient and proficient CYP1A1 expressing transformants is observed. BPD is cytotoxic to Cd induced CYP1A1 expressing XPA cells at > 10-fold lower doses than it is to Cd induced CYP1A1 expressing DNA repair normal cells. These data indicate that BPD is metabolized to a DNA damaging agent by induced CYP1A1. In contrast, benzo[a]pyrene-trans-7,8-diol-9,10-epoxide added to the media is only slightly more cytotoxic to DNA repair deficient than to proficient cells regardless of CYP1A1 expression. These studies demonstrate the usefulness of the CYP1A1 transformed fibroblasts in examining the cytotoxic effects of benzo[a]pyrene metabolites and suggest the future usefulness in examining the toxic effects of polycyclic aromatic hydrocarbons and other xenobiotics bioactivated by CYP1A1.
Carcinogenesis 1993 Aug
PMID:Expression of human cytochrome P450 1A1 in DNA repair deficient and proficient human fibroblasts stably transformed with an inducible expression vector. 835 49

Trichothiodystrophy (TTD) is a rare genetic disease associated in approximately 50% of patients with DNA repair deficiency analogous to that found in xeroderma pigmentosum group D (XP-D) patients. Although XP-D patients exhibit a very high level of skin cancer on sun-exposed parts, TTD is not associated with cancer. We analysed UV-induced mutations in TTD cells and compared them to data in XP-D in order to determine if the molecular mechanisms of mutagenesis can explain the discrepancies between these two syndromes. We first immortalized a fibroblast TTD line with an ori(-)-SV40 plasmid. To investigate the kinds of mutations induced in TTD cells, we used an UV-irradiated (at 254 nm) shuttle vector carrying the supF tRNA gene as a target. We compared our data with those published by others with the same pZ189 vector in normal and XP-D fibroblast lines (Bredberg et al., Proc. Natl. Acad. Sci. USA, 83, 8273-8277; Seetharam et al., J. Clin. Invest., 80, 1613-1617). The frequency of mutants increased linearly with UV dose and the slope was > 4 times steeper in TTD cells than that observed in normal cells. The mutation frequency was almost identical between XP-D and TTD cells. Sequence analysis of the supF tRNA gene showed that 96% of mutations obtained in TTD cells are base substitutions. Single base substitutions were found in 62% of mutants in TTD cells while they corresponded to 86% in XP-D cells. The frequency of multiple mutations in TTD cells (26%) was similar to that in normal cells (27%) and much higher than that in XP-D cells (9%). Despite the fact that the same gene is mutated in TTD and XP patients, the molecular characteristics of mutagenesis are not identical. The fact that the frequency of mutations in TTD and XP cells are similar shows that a high level of UV-induced mutations is therefore not always directly related to cancer-proneness. Other factors such as catalase activity and immuno-surveillance may intervene in cancer incidence.
Carcinogenesis 1993 Jul
PMID:UV-induced mutations in a shuttle vector replicated in repair deficient trichothiodystrophy cells differ with those in genetically-related cancer prone xeroderma pigmentosum. 839 42

Previous work from our laboratory has shown that mitochondria are able to repair N-methylpurines formed by methylnitrosourea (MNU). However, it is unclear as to whether repair mechanisms that remove this type of lesion in nuclear DNA also remove these adducts in mitochondria. To address this question, we studied repair of MNU-induced N-methylpurines in the mitochondrial DNA from xeroderma pigmentosum complementation group D (XP-D) cells using quantitative Southern blot analysis and 32P-end-labeling techniques. These cells have been reported to be defective in the repair of this type of lesion in their nuclear genome. WI 38 cells were used as normal controls for these studies. Both XP-D fibroblasts and WI 38 cells were exposed to 0.5 mM MNU for 1 h. Following an 8 h repair period, 61% of N-methylpurines were repaired in the mitochondrial genome of XP-D cells and 39% of these lesions were repaired in WI 38 cells. After 24 h, XP-D cells had repaired 77% of the N-methylpurines in their mitochondrial genome, while WI 38 cells had 44% repair of this type of damage. During this same 24 h time period, 81.5% of the N7-methylguanines had been removed from the total cellular DNA of the WI 38 cells compared to only 38.3% repair of this lesion in the XP-D cells. Thus, XP-D cells, though deficient in the repair of N-methylpurines in their nuclear genome, are proficient in the repair of this type of damage in their mitochondria, suggesting that the mechanisms to repair N-methylpurines in the nuclear and mitochondrial genomes of these cells are different.
Carcinogenesis 1993 May
PMID:Repair of N-methylpurines in the mitochondrial DNA of xeroderma pigmentosum complementation group D cells. 850 84

Cisplatin is a chemotherapeutic agent known to cause DNA damage. The cytotoxicity of this drug is believed to result from the formation of DNA intrastrand adducts (IA) and DNA interstrand crosslinks (ICL). While there are many studies on DNA repair of cisplatin damage at the overall level of the genome in various human cell lines, there is little information on the gene-specific repair. In this report, we have measured the formation and repair of cisplatin induced DNA adducts in the dihydrofolate reductase (DHFR) and ribosomal RNA (rRNA) genes in three cell lines: normal human fibroblasts, Fanconi's anemia complementation group A (FAA) and Xeroderma pigmentosum complementation group A (XPA). It is generally thought that XPA cells lack nucleotide excision repair and that FAA cells are deficient in the repair of DNA ICL. We find that normal human fibroblast cells repair 84% of the ICL in the DHFR gene after 24 h, whereas XPA and FAA cell lines only repaired 32 and 50% of the ICL respectively. Furthermore, 69% of the cisplatin IA in the DHFR gene were repaired in 24 h in normal human fibroblasts compared to 22% for XPA and 24% for FAA cells. The repair of the rRNA gene was less efficient than in the DHFR gene, but the relative pattern between the different cell lines was similar to that of the DHFR gene. We thus find that FAA cells are deficient not only in the gene specific repair of cisplatin ICL, but also in the gene specific repair of the more common cisplatin IA. XPA cells are normally thought to be without any nucleotide excision repair capacity, but our data could support a slight ICL unhooking activity.
Carcinogenesis 1993 May
PMID:Deficient gene specific repair of cisplatin-induced lesions in Xeroderma pigmentosum and Fanconi's anemia cell lines. 850 85

Thiol redox status was determined in normal human skin fibroblasts and a DNA repair-deficient xeroderma pigmentosum (XP) fibroblast cell line (XP12BE, group A), and cytotoxic and genotoxic effects of the thiol-reactive aldehyde acrolein were studied in these cell types. Normal cells contained higher amounts of the reduced glutathione and cysteine respectively, and higher amounts of these thiols as protein-bound disulfides than the XP cells. However, in both cell types total glutathione was present in 6- to 7-fold higher amounts than total cysteine, and total protein thiols corresponded to approximately 30% of total thiols. A 1 h exposure to acrolein caused a quantitatively similar depletion of reduced glutathione and free protein thiols in both cell types, without causing changes in the thiol redox state. However, acrolein caused higher toxicity measured as trypan blue exclusion, and also a higher extent of DNA single-strand breaks in the XP cells than in the normal cells. Exposure to acrolein, followed by incubation in fresh medium resulted in continued formation of DNA single-strand breaks in the normal cells, whereas no such accumulation occurred in the XP cells. In the normal cells, the DNA single-strand breaks accumulated to a similar extent as in the presence of 1-beta-D-arabinofuranosyl-cytosine and hydroxyurea, i.e. two agents which together efficiently inhibit DNA repair synthesis. The results indicate quantitative and qualitative differences in the thiol redox state between normal and XP cells, and that these differences may contribute to the higher cytotoxicity and genotoxicity of acrolein in XP cells. Moreover, the results indicate that acrolein is a potent inhibitor of DNA excision repair.
Carcinogenesis 1993 May
PMID:Thiol status and cytopathological effects of acrolein in normal and xeroderma pigmentosum skin fibroblasts. 850 92

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