bluuebunny/crossref_metadata_2025_split huggingface dataset:
High expression of cytochrome P450 2a‐5 (coumarin 7‐hydroxylase) in mouse hepatomas
Authors: Kobliakov Valery , Kulikova Ludmila , Samoilov Dimitri , Lang Matti A. 
Published: February 2007

AbstractA high level of Cyp2a‐5 was found in spontaneous and transplanted mouse hepatomas compared with normal liver. Increased expression of Cyp2a‐5 was associated with an increase in coumarin 7‐hydroxylation, a marker activity of Cyp2a‐5, and the corresponding mRNA, suggesting that regulation of Cyp2a‐5 in hepatomas is pretranslational. In contrast, the total P450 content and arylhydrocarbon hydroxylase and amidopyrene demethylase activities decreased. Pyrazole, a strong inducer of Cyp2a‐5 in normal mouse livers, also increases this isozyme in hepatomas. A parallel increase in the corresponding mRNA suggests that pyrazole, like the formation of hepatomas, affects the regulation of Cyp2a‐5 pretranslationally.
Preferential alteration of inducible gene expression in vivo by carcinogens that induce bulky DNA lesions
Authors: Hamilton Joshua W. , Louis Claudine A. , Doherty Kristen A. , Hunt Steven R. , Reed Michael J. , Treadwell Melinda D. 
Published: February 2007

AbstractOur laboratory is interested in whether chemical carcinogen—induced DNA damage is nonrandomly distributed in the genome, i.e., “targeted,” at the level of individual genes. To examine this, we have been investigating whether carcinogen treatment in vivo differentially alters the expression of specific genes. In this study, we examined the effects of four model carcinogens that induce bulky lesions in DNA—benzo[a]pyrene (B[a]P), aflatoxin B1 (AFB1), 7,12‐dimethylbenz[a]anthracene (DMBA), and 2‐acetylaminofluorene (AAF)—on the steady‐state mRNA expression of several constitutive and drug‐inducible genes in vivo. We specifically tested the hypothesis that carcinogen‐induced DNA damage is preferentially targeted to inducible genes relative to constitutively expressed genes using the chick embryo as a simple in vivo test system. In summary, the four carcinogens had no effect on the steady‐state mRNA expression of constitutively expressed β‐actin, transferrin, or albumin genes over a 24‐h period after a single dose of each carcinogen. In contrast, each of these same treatments significantly altered the mRNA expression of two glutethimide‐inducible genes, ALA synthase and CYP2H1. Both the basal expression of these genes and their drug‐inducible expression was altered. B[a]P and AFB1 had similar effects on expression of the two inducible genes and caused similar levels of covalent adducts in total DNA, even though the administered doses differed by 30‐fold. B[a]P metabolism, B[a]P binding to DNA, and the basal expression of CYP2H1 were similar in liver and lung. However, B[a]P significantly altered basal CYP2H1 mRNA expression in liver, a tissue in which this gene is highly inducible by glutethimide, and had no effect on basal CYP2H1 mRNA expression in lung, a tissue in which this gene is not drug‐inducible. These data support the hypothesis that inducible gene expression is a target for carcinogen‐induced DNA damage in vivo. © 1993 Wiley‐Liss, Inc.
Activation of distinct multidrug‐resistance (P‐glycoprotein) genes during rat liver regeneration and hepatocarcinogenesis
Authors: Teeter Larry D. , Estes Marc , Chan John Y. , Becker Frederick F. , Kuo M. Tien , Atassi Hammad , Sell Stewart 
Published: February 2007

AbstractThe multidrug transporter P‐glycoproteins are encoded by three multidrug‐resistance (mdr) genes in rodents, designated mdr1a (mdr3), mdr1b (mdr1), and mdr2. Only the first two genes are functionally related to multidrug resistance. Activation of rodent mdr genes during liver regeneration and hepatocarcinogenesis has been reported. In mice, mdr1a is activated in hepatocellular carcinomas (HCCs) produced by various carcinogenic protocols, whereas both mdr1a and mdr2 are activated during liver regeneration. In this communication, we report isolating three gene‐specific probes for the rat mdr homologues, which were used as probes in an RNase protection assay to demonstrate that mdr1b mRNA was expressed in HCCs induced by two different protocols. Furthermore, high levels of hepatic mdr1b mRNA but only moderate levels of mdr1a and mdr2 mRNA were seen in preneoplastic lesions in rats treated with 2‐acetylaminofluorene. Likewise, highly elevated levels of hepatic mdr1b mRNA but only moderately increased levels of mdr1a and mdr2 mRNA were seen after partial hepatectomy. Nevertheless, the general patterns of tissue‐specific expression of these three mdr genes were similar in rats and mice. These results reveal a complex hepatic gene expression pattern during hepatocarcinogenesis and hepatic proliferation for this conserved gene family in rodents.
Characterization of a nuclear factor, papilloma enhancer binding factor‐1, that binds the long control region of human papillomavirus type 16 and contributes to enhancer activity
Authors: Cuthill Scott , Sibbet Gary J. , Campo M. Saveria 
Published: February 2007

AbstractHuman papillomavirus type‐16 (HPV‐16) is an epitheliotropic DNA tumor virus associated with the development of cervical carcinoma. The expression of HPV‐16 early genes is driven by a cell‐type—specific enhancer located in the long control region of the viral genome. We identified an element within the HPV‐16 minimal enhancer that has enhancer activity and binds a nuclear factor, designated papillomavirus enhancer binding factor‐1 (PEF‐1). The element (called FP‐F by us and fp5e by Gloss et al. (EMBO J 6:3735–3743, 1987)) was originally identified as a footprint by DNase I protection experiments. The PEF‐1 binding site is centered around a CCAAT box—like CCAAC element. Introduction of A→T transversions into the CCAAC element of fp5e abolished binding of PEF‐1 and concomitantly abolished enhancer function. fp5e resembles binding sites for the transcriptional activators CTF/NF‐1 and AP‐2; however, we showed that neither of these factors interacted with this element. PEF‐1 has an apparent molecular weight of about 110 kDa, and we propose that it is a novel factor involved in the transcriptional activation of HPV‐16 gene expression.
Gene expression screening for specific genes associated with mouse mammary tumor development
Authors: Zhang Lixin , Medina Daniel 
Published: February 2007

AbstractThe preneoplastic hyperplastic alveolar nodule is a frequent and well‐characterized precursor to mammary tumors in the mouse. Although the biological characteristics of the preneoplastic state have been understood for many years, the molecular alterations associated with preneoplasia and tumorigenicity are unknown. We applied the technique of differential display of mRNA to two closely matched cell populations of mammary preneoplasias that differed only in their tumorigenic potential. Two mRNAs were isolated that were overexpressed only in tumorigenic preneoplasias and in tumors and not in normal pregnant mammary gland or in nontumorigenic preneoplasias. Partial nucleotide sequencing indicated that one of the mRNAs had not yet been described, whereas the second mRNA was highly homologous to a relatively uncharacterized gene termed pT‐2. These results illustrate the utility of the differential display method for isolating and identifying uniquely expressed genes from tissues maintained in the microenvironment where tumors arise naturally.
Mutational specificities of environmental carcinogens in the lacl Gene of Escherichia coli VII: The host‐mediated assay and its comparison with in vitro mutagenesis induced by 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone
Authors: Jiao Jianli , Glickman Barry W. , Zielenska Maria , Guttenplan Joseph B. , Xin Liu‐Yu , Anderson Marshall W. 
Published: February 2007

AbstractTo investigate the influence of different types of metabolic activation (9,000 x g supernatant (S9) activation vs. a host‐mediated approach) on 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK)‐induced mutational specificity, we determined by DNA sequencing the distribution of forward mutations recovered in the N‐terminal region of the lacl gene of Escherichia coli. After activation with the S9 liver fraction from rats treated with Aroclor 1254, a diverse spectrum of mutations was recovered, with 55% of the events being G:C→A:T transitions. In contrast, after the host‐mediated assay in mice, G:C→A:T transitions accounted for over 94% of the mutations recovered. Generally, NNK metabolism can proceed through two distinct pathways, involving either α‐methyl or methylene hydroxylation. These two pathways produce different distributions of DNA damage. The difference in the mutational spectra we observed thus likely reflects the difference in the contributions of each pathway under the two different treatment conditions.
Effect of gastrin‐releasing peptide on the pancreatic tumor cell line (capan)
Authors: Avis Ingalill , Cuttitta Frank , Treston Anthony M. , Mulshine James L. , Jett Marti , Kasprzyk Philip G. , Maneckjee Rhoda 
Published: February 2007

AbstractGastrin‐releasing peptide (GRP) has previously been shown to be an autocrine growth factor for small cell lung cancer, and our objective in the study presented here was to determine whether GRP has a similar role in pancreatic cancer. Using 125I‐GRP, we demonstrated binding to specific, saturable, high‐affinity sites (Kd=1 nM; Bmax=245 fmol/mg protein) in membrane preparations from the pancreatic tumor cell line Capan. The receptors were found to be biologically active. In whole cells, a GRP analogue bound to these receptors and stimulated rapid transfer of tritium from the tritiated lipid inositol pool to inositol triphosphates. Exogenous GRP addition stimulated incorporation of [3H]thymidine into DNA 20–60%. This stimulatory effect was blocked by the addition of a monoclonal antibody that complexed specifically with the receptor‐binding portion of the peptide. In addition, the monoclonal antibody inhibited the growth of Capan cells in an in vitro growth assay without exogenous peptide. Bombesin receptor—specific antagonists also inhibited growth in a similar fashion. These data suggest that paracrine production of GRP may be important in pancreatic tumor growth, or that low‐levels of a GRP‐like peptide may play an autocrine role in this tumor. © 1993 Wiley‐Liss, Inc.
Dose‐ and time‐dependent expression of transforming growth factor‐β1 mRNA and protein in mouse epidermis and papillomas after repeated topical application of benzo[a]pyrene
Authors: Sherman James H. , Miller Marian L. , Albert Roy E. , Baxter C. Stuart 
Published: February 2007

AbstractTopical weekly application of 64 μg of benzo[a]pyrene (BAP) for 4 wk induced transforming growth factor (TGF)‐β1 mRNA in the epidermis of Swiss (ICR) mice, with a maximum at 6–12 h after the last treatment. The increase in TGF‐β1 mRNA concentration was accompanied by an increase in immunohistochemically detectable intracellularly localized TGF‐β1 protein in the suprabasal epidermis and by the appearance of extracellularly localized TGF‐β1 in the basal layers. A dose rate of 16 μg/wk for 4 wk was unable to induce the same response. In contrast, after 20 weekly topical applications of 16 or 64 μg of BAP, an increase in TGF‐β1 mRNA concentration and the appearance of extracellularly localized protein in the epidermis were observed. These changes in TGF‐β1 expression were paralleled by changes in epidermal morphology. A similar group of animals treated with 4 μg of BAP/wk for 20 wk did not respond differently from untreated controls. Papillomas resulting from treatment with 16 or 64 μg of BAP/wk for 28 wk stained for intracellularly localized TGF‐β1 predominantly in the differentiating and nondividing layers. Papillomas stained for extracellularly localized TGF‐β1 solely in the less differentiated and dividing cells. These results suggest that tumorigenesis by BAP involves the induction of cumulative changes in epidermal TGF‐β1 mRNA and protein concentrations as well as alterations in skin morphology associated with a tumor‐promotion process.
Further analysis of c‐Ha‐ras mutations in papillomas initiated by several polycyclic aromatic hydrocarbons and papillomas from uninitiated, promoter‐treated skin in sencar mice
Authors: Digiovanni John , Beltrán Linda , Rupp Amy , Gill Rosalynn D. , Harvey Ronald G. 
Published: February 2007

AbstractIn this study we analyzed the mutations in c‐Ha‐ras from skin papillomas initiated with benzo[a]pyrene (B[a]P), 7‐methylbenz[a]anthracene (7‐MBA), and 10‐fluoro‐7‐methylbenz[a]anthracene (10‐F‐7‐MBA) and from papillomas induced by treatment with tumor promoter alone. Among the papillomas induced by treatment with tumor promoter alone, 56% (nine of 16) had mutations in c‐Ha‐ras. These mutations were found primarily in codon 61 and included both A182→T and A182→G mutations. In addition, one promoter‐induced tumor had a G35→A mutation in codon 12, and one had a G37°C mutation in codon 13. The other promoter‐induced papillomas did not have detectable mutations in codons 12, 13, or 61. Most of the B[a]P‐initiated papillomas (77%; 10 of 13) did not have detectable mutations in c‐Ha‐ras codons 12, 13, or 61. However, three of these B[a]P‐initiated papillomas had c‐Ha‐ras codon 13 mutations; one had a G37°C transversion and two had G38→ T transversions. Most of the 7‐MBA—initiated tumors and all of the 10‐F‐7‐MBA—initiated tumors had an activated c‐Ha‐ras gene [nine of 10 (90%) and 11 of 11 (100%), respectively]. These mutations were almost exclusively A182→ T transversions in codon 61 except for two 7‐MBA—initiated papillomas that had G37°C transversions in codon 13. The results suggest that more than one mechanism may contribute to activation of c‐Ha‐ras by polycyclic aromatic hydrocarbons (PAHs) in mouse skin. Furthermore, the absence of c‐Ha‐ras mutations in most B[a]P‐initiated papillomas, as well as in a significant fraction of those induced by tumor promoter alone, suggests that there may be other molecular targets involved in tumor initiation by PAHs in mouse skin.
Absence of MDM‐2 gene amplification in experimentally induced tumors regardless of p53 status
Authors: Saez Guillermo T. , Oliva Maria R. , Mangues Ramon , Pellicer Angel 
Published: February 2007

AbstractTo assess the generality of the hypothesis that murine double‐minute‐2 (MDM‐2) gene amplification complements the absence of p53 mutation during tumor development, we analyzed 143 murine tumors induced by a variety of carcinogenic agents in two different mouse strains. Only three of 143 tumors showed p53 genetic alterations and none showed MDM‐2 amplification, indicating the existence of alternative pathways that permit tumor cells to bypass p53–MDM‐2 control. © 1994 Wiley‐Liss, Inc.
Allele loss and point mutation in codons 12 and 61 of the c‐Ha‐ras oncogene in carcinogen‐transformed human breast epithelial cells
Authors: Zhang Pei‐Li , Calaf Gloria , Russo Jose 
Published: February 2007

AbstractThere is significant evidence that the ras oncogene plays a role in experimental mammary carcinogenesis; the evidence in human breast cancer, however, is more limited. We induced the expression of transformation phenotypes in the human breast epithelial cell line MCF‐10F with the chemical carcinogens 7,12‐dimethylbenz[a]‐anthracene, N‐methyl‐N‐nitrosourea, N‐methyl‐N‐nitro‐N′‐nitrosoguanidine, and benzo[a]pyrene. This work was designed to clarify whether chemically induced neoplastic transformation correlates with alterations in the ras gene. MCF‐10F cells have two c‐Ha‐ras alleles, identified by 1.0‐kb and 1.2‐kb restriction fragments. Treatment with carcinogens resulted in the loss of one of the alleles (1.0 kb). Polymerase chain reaction–amplified DNA from all carcinogen‐treated cells was analyzed for point mutations in c‐Ha‐ras at codons 12 and 61. All of the carcinogens induced a mutation of the remaining allele at the first position of codon 12 (GGCÀC). Another frequent mutation occurred at the first position of codon 61 (CAG←GAG). The changes in c‐Ha‐ras were associated with the emergence of colony formation in agar‐methocel, but no specific changes in this gene correlated with the emergence of invasiveness or tumorigenesis, indicating that other genes may be involved in the process. © 1994 Wiley‐Liss, Inc.
Screening for p53 mutations in c3h/he mouse liver tumors derived spontaneously or induced with diethylnitrosamine or phenobarbitone
Authors: Rumsby Paul C. , Davies Margaret J. , Evans John G. 
Published: February 2007

AbstractDistinct differences have been described in the development of C3H/He mouse liver tumors induced by the genotoxic carcinogen diethylnitrosamine (DEN) and by the nongenotoxic agent phenobarbitone (PB) in terms of pathology and the frequency of mutation at codon 61 of the Ha‐ras oncogene. To further define the mechanisms involved, we screened the tumor suppressor gene p53 for mutations in exons 5, 7, and 8 using polymerase chain reaction (PCR)–single‐strand conformation polymorphism (SSCP) analysis. Nearly all the mutations so far described have been found within these three exons. In this study a total of six spontaneous tumors, eight tumors induced by PB, 14 tumors induced by DEN, and five samples of normal liver tissue were screened, and no mutations were found in any of the tumors examined. The positive control, the plasmid LTRp53cG (val), had a point mutation in exon 5 that was detected by PCR‐SSCP. Since many of the tumors were late‐stage hepatocellular carcinomas, we concluded that mutations in exons 5, 7, and 8 of the p53 gene do not play an important role in the development of chemically induced liver tumors in the C3H/He mouse. © 1994 Wiley‐Liss, Inc.
The effects of bile acids on phospholipase c activity in extracts of normal human colon mucosa and primary colon tumors
Authors: Nomoto Koji , Morotomi Masami , Miyake Masami , Xu Ding‐Bang , Logerfo Paul P. , Bernard Weinstein I. 
Published: February 2007

AbstractPhospholipase C (PLC) activity and its response to stimulation by bile acids was assayed in cellular extracts from 16 primary human colon tumors of various Duke′s stages and paired adjacent normal mucosal samples. In the absence of bile acid, there was negligible degradation of phosphatidylinositol (PI) 1‐stearoyl‐2‐[14C]‐arachiodonoyl by tumor or normal tissue, but the addition of deoxycholic acid (DCA) or taurocholic acid (TCA) resulted in concentration‐dependent and time‐dependent stimulation of diacylglycerol (DAG) formation at optimal concentrations of 2 mM DCA and 4 mM TCA. Triton X‐100 (0.125–1.0%) inhibited rather than enhanced the PI‐degrading activity of these extracts, indicating that the stimulatory effects of DCA and TCA were not simply due to a detergent effect. Under the same assay conditions there was only a small amount of labeled monoacylglycerol or free arachidonic acid produced by extracts incubated in the absence or presence of DCA or TCA. No major differences in DAG production from PI were seen between paired samples of normal colon mucosa and primary colon tumors, in assays done in the presence of 2 mM TCA. Extracts from tumors in the distal part of the colon had higher activity than those from the proximal colon. This was also true for the extent of release of free arachidonic acid from labeled PI. Under the same conditions, labeled phosphatidylcholine or phosphatidylethanolamine did not serve as substrates for the colon mucosa or tumor extracts. Nor was there significant hydrolysis of the labeled DAG (1‐stearoyl‐2‐14C‐arachidonoylglycerol) by normal colon mucosa or tumor extracts, in the absence or presence of DCA or TCA. On the other hand, a low level of DAG lipase activity was detected in the presence of Triton X‐100. These findings provide the first evidence that normal human colon mucosa and primary colon tumors contain a PI‐specific PLC activity that is markedly stimulated by bile acids. Our results also suggest that bile acids may enhance colon carcinogenesis by acting on this enzyme system, thereby influencing signal transduction pathways in the target cells. © 1994 Wiley‐Liss, Inc.
In vitro growth suppression and morphological change in a human renal cell carcinoma cell line by the introduction of normal chromosome 3 via microcell fusion
Authors: Yoshida Mitsuaki A. , Shimizu Motoyuki , Ikeuchi Tatsuro , Tonomura Akira , Yokota Jun , Oshimura Mitsuo 
Published: February 2007

AbstractCytogenetic and molecular studies of human renal cell carcinoma (RCC) have suggested that the genetic and functional losses of one or more putative tumor suppressor genes on the short arm of chromosome 3 play a crucial role in the development of this disease. To examine whether the introduction of chromosome 3 has any effects on the biology of RCC cells, we introduced either chromosome 3, 7, or 11 from normal human fibroblasts into a newly established human RCC cell line with loss of heterozygosity for 3p, via microcell‐mediated chromosome transfer. Microcell hybrids containing an introduced, intact chromosome 3 showed a significant reduction in in vitro growth rate and saturation density together with morphological alteration; these properties were not altered in microcell hybrids containing an introduced chromosome 7 or 11. During long‐term cultivation, one of the clones that had lost the introduced chromosome 3 showed growth properties and morphology similar to those of the parental cell lines. Thus, our findings provide additional evidence for the presence of a putative tumor suppressor gene or genes on normal chromosome 3p and indicate that the gene is a dominant, negative growth regulator whose loss promotes progressive features of the neoplastic phenotype. © 1994 Wiley‐Liss, Inc.
Focal transgene expression associated with papilloma development in v‐Ha‐ras–transgenic TG.AC mice
Authors: Hansen Laura A. , Tennant Raymond 
Published: February 2007

AbstractThe homozygous transgenic mouse line TG.AC contains a v‐Ha‐ras transgene and rapidly develops epidermal papillomas in response to either wounding or treatment with tumor promoters such as 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA). The transgenic v‐Ha‐ras protein product was detected in all papillomas removed from TPA‐treated TG.AC mice but not in vehicle‐or TPA‐treated TG.AC skin without tumors. In situ hybridization demonstrated that focal expression of the transgene was limited to regions of papilloma development and further localized the expression of the transgene message to the epidermal component of the papillomas, with the strongest signal in the basal epidermoid cells. Cellular proliferation, as indicated by immunohistochemical staining for proliferating‐cell nuclear antigen (PCNA), was similarly localized primarily to basal epidermoid cells and, to a lesser extent, stratum spinosum cells in all papillomas analyzed. Cells that stained positively for PCNA were much more common in the papillomas than in the surrounding, normal‐appearing skin. The focal nature of papilloma development was also evidenced by protein kinase C activity and hyperplasia after TPA treatment. As early as 18 d after the start of TPA treatment, focal hyperplasias associated with the follicular epidermis were observed in TG.AC but not nontransgenic FVB/N skin; these hyperplasias were assumed to be the precursors of the epidermal papillomas. To explain the development of transgene‐expressing tumors from apparently transgene‐negative, normal‐appearing skin, we hypothesize that the papillomas arise from the clonal expansion of focal areas of epidermal cells that overexpress the transgene. We also propose that the TG.AC line is an excellent model for studying very early events in papillomagenesis. © 1994 Wiley‐Liss, Inc.