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

Expression plasmids (pKCPS-CAT) containing carbamyl phosphate synthetase (CPS I) upstream sequences of different lengths were constructed, and the function and characteristics of the sequences were studied with the CAT assay. Results showed that the CPS I upstream sequences exerted highly tissue-specific control on CPS I gene expression, and the -113 approximately -38 bp region relative to the cap site was found to be indispensable for CPS I gene transcription. The -1700 approximately -161 bp region contains sequences which confer an enhancing effect on CPS I gene transcription. Dexamethasone and thioproline (a differentiation inducer) showed enhancing effects on CPS I gene transcription in hepatoma cells. These results would have significance in studies on the gene regulation of CPS I associated with the mechanism of hepatocyte differentiation and carcinogenesis.
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PMID:Functional analysis of the CPS I upstream sequences with a cat assay. 166 83

The process of mouse skin tumor formation is subdivided into three operational stages. These stages include initiation, promotion and progression. Ionizing radiation has been found to be a weak initiating agent in the production of malignant squamous cell carcinomas, a complete carcinogen and an agent effective in causing tumor progression. Four skin tumor histologies have been seen with ionizing radiation: benign papillomas, squamous (SCC) and basal (BCC) cell carcinomas and fibrosarcomas. Distinct non-ras transforming genes have been detected in radiation initiated SCCs. A benign papilloma cell line (308) was used as a model system to study ionizing radiation induced progression. A variant 308 cell line (308 10 Gy 5) derived by irradiation of the parental 308 cell has been characterized. The 308 10 Gy 5 cells unlike the parental 308 cells form malignant tumors in athymic nude mice upon subcutaneous injection. The variant 308 10 Gy 5 cells unlike the parental cells also show by northern analysis high steady state levels of the following gene transcripts: stromelysin, metallothionein II A and the proto-oncogenes c-fos and c-jun. Transient transfection studies with a chimeric mouse stromelysin promoter sequence upstream of a chloramphenicol (CAT) reporter gene into 308 and 308 10 Gy 5 cells indicated that the stromelysin promoter was constitutively active in the 308 10 Gy 5 but not in the 308 cells. The ability to divide the process of carcinogenesis into multiple stages in the mouse skin mode has facilitated mechanistic studies that may elucidate the molecular pathways involved in radiation induced tumor development.
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PMID:Molecular events involved in ionizing radiation induced skin carcinogenesis. 182 59

The mechanism of action of tumor promoters may involve the modulation of gene expression, e.g., the induction of ornithine decarboxylase (ODC). The tumor promoter phorbol-13-myristate-12-acetate (PMA) induces chromosomal damage via the intermediacy of active oxygen species which may trigger the activation of certain genes. Therefore, we have studied the effect of antioxidants on the induction of ODC by PMA, medium change only and medium change plus PMA in mouse mammary tumor cells Mm5mt/C1. CuZn-superoxide dismutase (SOD, a scavenger of superoxide radicals), catalase (CAT, a scavenger of hydrogen peroxide) and mannitol (a scavenger of hydroxyl radicals) suppressed ODC induction under all three conditions. The relative inhibitory potency of the antioxidants was always SOD less than CAT less than mannitol less than SOD + CAT. Maximal suppression by SOD + CAT was approximately 50%. It is concluded that active oxygen species play a role in ODC induction by factors contained in serum and by PMA.
Carcinogenesis 1983 Nov
PMID:The induction of ornithine decarboxylase by phorbol 12-myristate 13-acetate or by serum is inhibited by antioxidants. 664 Aug 44

The promoter of the rat alpha-fetoprotein (AFP) gene, which makes the expression of the developmentally regulated AFP gene specific to the liver, is a putative target for transcription factors of the CAAT/enhancer-binding protein (C/EBP), hepatocyte nuclear factor-1 (HNF-1) and nuclear factor-1 (NF-1) families. We have evaluated the influence of these factors on the activity of the AFP promoter by transfection of HepG2 hepatoma cells with the appropriate expression vector plus a CAT plasmid under the control of the AFP promoter. A similar plasmid bearing the rat albumin promoter was used as a control. C/EBP alpha, C/EBP beta and D-binding protein (DBP) acted as trans-activators on the AFP promoter, whereas liver inhibitory protein (LIP), a truncated form of C/EBP beta, was a potent negative regulator of the promoter. C/EBP alpha also bound to and stimulated the activity of the AFP enhancer at -2.5 kb. Interestingly, HNF-1 beta was found to be more potent than HNF-1 alpha in activating the AFP promoter. This effect was specific, as it did not occur with the rat albumin promoter. HNF-1 beta, which is produced earlier than HNF-1 alpha during liver development, would thus have the greater influence on the AFP promoter in early development. Both HNF-1s allowed expression of the AFP promoter in cells of nonhepatic origin. Overexpression of NF-1 induced a specific decrease in the activity of the AFP promoter. This strongly suggests that competition between NF-1 and HNF-1 for binding to their overlapping binding sites on the AFP promoter is critical for modulating its activity. Thus changing combinations of these trans-acting factors may tightly modulate the AFP promoter activity in the course of liver development and carcinogenesis.
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PMID:Members of the CAAT/enhancer-binding protein, hepatocyte nuclear factor-1 and nuclear factor-1 families can differentially modulate the activities of the rat alpha-fetoprotein promoter and enhancer. 751 71

The oncodevelopmentally regulated alpha-fetoprotein (AFP) gene offers a very good model system to better understand the molecular mechanisms which dictate the specificity of gene expression in liver and control its tight modulation in the course of development and carcinogenesis. Transcription factors of the CCAAT/enhance-binding protein (C/EBP), hepatocyte nuclear factor-1 (HNF-1), and nuclear factor-1 (NF-1) families can bind in vitro to the promoter of the rat AFP gene, which makes the expression of the AFP gene specific to the liver. We have evaluated the influence of some of these factors on the activity of the AFP promoter by transfection of HepG2 hepatoma cells with the appropriate expression vector plus a CAT plasmid under the control of the AFP promoter. A similar plasmid bearing the rat albumin promoter was used as a control. C/EBP alpha, and C/EBP beta acted as transactivators on the AFP promoter, while LIP, a truncated form of C/EBP beta, was a potent negative regulator of the promoter. Interestingly, HNF-1 beta was found to be more potent than HNF-1 alpha in activating the AFP promoter in the HepG2 cells. This effect was highly promoter and cell specific since it did not occur with the rat albumin promoter or in Chinese hamster ovary cells. HNF-1 beta, which is produced earlier than HNF-1 alpha during liver development, would thus have the greater influence on the AFP promoter in early development. Our results pointed to a key role that NF1 might play in the functioning of the AFP promoter. Indeed, overexpression of NF1 induced a specific decrease in the activity of the AFP promoter. Competition between NF1 and HNF-1 for binding to their overlapping binding sites on the AFP promoter would be critical for modulating its activity.
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PMID:[Several transcription factors participate in the functioning of the alpha-fetoprotein gene promoter]. 754 16

The XPA gene was initially cloned based on the ability of its cDNA to improve survival of cells from xeroderma pigmentosum complementation group A (XP-A) patients following irradiation of the cells with UV. We used plasmid host cell reactivation assays to compare UV mutagenesis and the proficiency of DNA repair in a cell line from an XP-A patient, XP2OS(SV40), two derivative cell lines stably expressing XPA cDNAs and in a DNA repair proficient human cell line. Expression of XPA protein in XP2OS cells allowed them to repair UV-treated plasmid pRSVCAT, increasing activity of the damaged CAT marker gene > 100-fold to levels produced by similarly damaged plasmids in normal cells. Expression of the XPA protein in XP2OS cells improved replication of the UV-treated shuttle vector pSP189, increasing plasmid survival and decreasing plasmid mutation frequency to the levels measured in normal cells. The sequence locations of most mutation hotspots in the plasmid marker gene were similar for the three cell lines and the differences did not correlate with the DNA repair status of the cells. This suggests that the location of mutation hotspots is not directly influenced by DNA repair. Expression of the XPA protein did cause a shift in the types of mutations seen in the plasmid gene. In the XP2OS cells > 95% of the plasmid mutations were G:C-->A:T transition mutations. In contrast, XP2OS cells expressing XPA produced other types of mutations: three times as many transversion mutations and a 12-fold increase in mutations at A:T base pairs. Furthermore, the distribution of these types of mutations was similar to the proportions measured in normal cells. Strikingly similar patterns of transition and transversion mutations were found by examination of reports of XP and non-XP skin carcinomas containing mutations in the p53 tumor suppressor gene, suggesting that the repair status of the cells influenced mutagenesis associated with these skin cancers. Our data suggest that loss of XPA gene function may be sufficient to effect the quantitative and qualitative changes in mutagenesis associated with the large increase in skin cancers seen in XP-A patients.
Carcinogenesis 1995 Jul
PMID:Expression of a transfected DNA repair gene (XPA) in xeroderma pigmentosum group A cells restores normal DNA repair and mutagenesis of UV-treated plasmids. 761 89

Expression plasmids (pKCPSx-CAT) containing carbamyl phosphate synthetase I (CPS I) upstream sequences of different lengths were constructed, and the function and characteristics of the sequences were studied with the CAT assay. The results showed that the CPS I upstream sequences exerted highly tissue-specific control on CPS I gene expression, and the -142- -38bp region relative to the cap site was found to be indispensable for CPS I gene transcription. The -1700- -161bp region contains sequences which confer an enhancing effect on CPS I gene transcription. Dexamethasone and thioproline (a differentiation inducer) showed enhancing effects on CPS I gene transcription in hepatoma cells. These results would have significance in studies on the gene regulation of CPS I associated with the mechanism of hepatocyte differentiation and carcinogenesis.
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PMID:[Functional analysis of the CPS I upstream sequences with a CAT assay]. 765 2

The regulation of p53 protein synthesis and p53-mediated gene transactivation were evaluated in cultured mouse keratinocytes maintained as basal cells or induced to differentiate by Ca2+ > 0.1 mM. p53 protein half-life, p53 protein synthesis and the level of p53 mRNA decreased during terminal differentiation, as detected by immunoprecipitation with a panel of p53-specific antibodies and Northern blotting. Thus differentiating keratinocytes have lower levels of p53 protein. This decline is not observed following growth arrest alone, or in papilloma cell lines which do not terminally differentiate in response to Ca2+. In contrast, the ability of endogenous p53 to transactivate transcription from the PG13 CAT plasmid increased during differentiation in vitro. This change in activity cannot be explained by changes in p53 conformation or nuclear localization. Consistent with these findings, mRNA for the p53-mediated genes WAF1 and mdm-2 increased with Ca(2+)-induced differentiation in a time dependent manner, suggesting activation of p53 contributes to the differentiated phenotype. However, p53-null mice exhibit histologically normal skin and epidermal keratinocytes from these mice express the appropriate markers of differentiation and suppression of DNA synthesis in vitro when the [Ca2+] is > 0.1 mM. The observation that proliferating cells have higher levels of p53 protein which is less active for its function than differentiated cell types could have a consequence for the selection of p53 gene mutations during carcinogenesis, depending upon the stage of differentiation of the tumor cell type.
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PMID:p53-mediated transcriptional activity increases in differentiating epidermal keratinocytes in association with decreased p53 protein. 778 75

In vitro differentiated hamster Clara cells were used to study the effects of lung carcinogens on the regulation of the c-jun oncogene. Northern blot analysis revealed a decrease in the expression of jun transcripts 24 h following the exposure of Clara cells to the direct acting forms of benzo[a]pyrene (BPDE*) or 5-methylchrysene (5MeCDE). To determine whether this decrease was mediated at the transcriptional level, we have used CAT reporter constructs driven by nested deletions of the 5' non-coding regulatory region of the c-jun oncogene. While BPDE was capable of activating certain regulatory domains of the c-jun promoter, this activation was not observed with either 5MeCDE or the less active lung carcinogens BADE or 6MeCDE. Analysis of enhancer elements identified the SP1 target site as a strong silencer after BPDE treatment. While positive regulatory element(s) mediating activation of c-jun by BPDE were localized within the promoter region up to -1639, further upstream sequences reduced this transcriptional activation. Thus, when the complete promoter region, up to -4500, was tested, no transcriptional activation was noted following BPDE treatment. These observations suggest that the regulation of c-jun in Clara cells exposed to potent lung carcinogens is mediated at the post-transcriptional level, possibly by reducing the stability and, in turn, the half life of c-jun mRNA. Overall, in contrast to the response of c-jun to numerous carcinogens and stress inducing agents noted in various other cell systems, our findings suggest the existence of a tissue-specific regulatory response for c-jun.
Carcinogenesis 1994 Dec
PMID:Regulation of c-jun by lung carcinogens in Clara cells of hamsters. 800 Dec 36

The mouse skin multistage model of carcinogenesis is an ideal system in which to study questions related to the timing of oncogene activation and inactivation of tumor suppressor genes. A number of laboratories have shown that an early event associated with chemical initiation of mouse skin tumors involves activation of the Harvey-ras oncogene. To approach the question of timing of loss of tumor suppressor genes in skin carcinogenesis, we have utilized a model system developed by Kulesz-Martin in which cloned mouse keratinocytes were initiated with DMBA and variant clones with benign or malignant phenotypes were developed. We have generated somatic cell hybrids between the parental clone and the variants to study the potential loss of tumor suppressor activity during the progression of cells from the initiated to benign and to the malignant phenotypes. Somatic cell hybrids generated between the parental, normal cell strain (i.e., 291) and a malignant cell variant (i.e., 05), that produces moderately differentiated squamous cell carcinomas (SCCs), failed to produce tumors indicating tumor suppressor activity in the 291 cells. The 291 cells and a benign papilloma producing variant (i.e., 09) were able to partially suppress in hybrids the tumorigenicity of another malignant cell line (i.e., 03) which produces poorly-differentiated SCCs. Suppression of 03 tumorigenicity by the benign tumor cell, 09, was less than that seen with the normal cell, 291. These results indicated two potentially different suppressor activities were inactivated during progression of normal 291 to malignant 03 cells. We have also obtained evidence that constitutive AP-1 activity plays a role in the maintenance of the malignant phenotype of SCC cell lines. Two different SCC cell lines, 308 10Gy5 and PDV, demonstrate constitutive AP-1 activity. To examine the role of this activity in malignant progression, we stably expressed a transactivation deletion mutant of the human c-jun gene in these cell lines. Expression of this mutant c-jun protein blocked transcriptional transactivation of AP-1 responsive reporter CAT constructs driven by jun, human collagenase, and the mouse stromelysin promoters. These malignant cells were not only inhibited in their AP-1 transactivation response, but also in their ability to form SCCs upon s.c. injection into athymic nude mice. These results support the idea that inhibition of AP-1-mediated transcriptional transactivation is in some cases sufficient to suppress the tumorigenic phenotype of malignant mouse epidermal cells.
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PMID:Oncogene activation and tumor suppressor gene inactivation during multistage mouse skin carcinogenesis. 813 4


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