bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dna polymerase arrest by adducted trivalent chromium
Authors: Bridgewater Laura C. , Manning Francis C. R. , Woo Elizabeth S. , Patierno Steven R. 
Published: February 2007

AbstractCarcinogenic chromium (Cr6+) enters cells via the sulfate transport system and undergoes intracellular reduction to trivalent chromium, which strongly adducts to DNA. In this study, the effect of adducted trivalent chromium on in vitro DNA synthesis was analyzed with a polymerase‐arrest assay in which prematurely terminated replication products were separated on a DNA sequencing gel. A synthetic DNA replication template was treated with increasing concentrations of chromium(III) chloride. The two lowest chromium doses used resulted in biologically relevant adduct levels (6 and 21 adducts per 1,000 DNA nucleotides) comparable with those measured in nuclear matrix DNA from cells treated with a 50% cytotoxic dose of sodium chromate in vivo. In vitro replication of the chromium‐treated template DNA using the Sequenase version 2.0 T7 DNA polymerase (United States Biochemical Corp., Cleveland, OH) resulted in dose‐dependent polymerase arrest beginning at the lowest adduct levels analyzed. The pattern of polymerase arrest remained consistent as chromium adduct levels increased, with the most intense arrest sites occurring 1 base upstream of guanine residues on the template strand. Replication by the DNA polymerase I large (Klenow) fragment as well as by unmodified T7 DNA polymerase also resulted in similar chromium‐induced polymerase arrest. Interstrand crosslinking between complementary strands was detected in template DNA containing 62, 111, and 223 chromium adducts per 1,000 DNA nucleotides but not in template containing 6 or 21 adducts per 1,000 DNA nucleotides, in which arrest nevertheless did occur. Low‐level, dose‐dependent interstrand cross‐linking between primer and template DNA, however, was detectable even at the lowest chromium dose analyzed. Since only 9% of chromium adducts resulted in polymerase arrest in this system, we hypothesized that arrest occurred when the enzyme encountered chromium‐mediated interstrand DNA‐DNA cross‐links between either the template and a separate DNA molecule or the template and its complementary strand in the same molecule. These results suggest that the obstruction of DNA replication by chromium‐mediated DNA‐DNA cross‐links is a potential mechanism of chromium‐induced genotoxicity in vivo. © 1994 Wiley‐Liss, Inc.
Alterations in the methylation status and expression of the raf oncogene in phenobarbital‐induced and spontaneous B6C3F1 mouse liver tumors
Authors: Ray Jean S. , Harbison Margaret L. , McClain R. Michael , Goodman Jay I. 
Published: February 2007

AbstractThe liver tumor‐prone B6C3F1 mouse (C57BL/6 ♂ × C3H/He♀), in conjunction with the more susceptible C3H/He paternal strain and the resistant C57BL/6 maternal strain, is an excellent model for studying the mechanisms involved in carcinogenesis. The study reported here indicated that the B6C3F1 mouse inherited a maternal raf allele containing a methylated site not present in the paternal allele. Seven days after partial hepatectomy or after administration of a promoting dose of phenobarbital (PB) for 14 d; raf in B6C3F1 mouse liver was hypomethylated. The additional methylated site in the allele inherited from C57BL/6 was not maintained. The methylation status of raf in the liver of the C57BL/6 mouse was not affected by PB treatment. This indicates that the B6C3F1 mouse is less capable of maintaining methylation of raf than the C57BL/6 strain is. In both PB‐induced and spontaneous B6C3F1 liver tumors, raf was hypomethylated in a nonrandom fashion. The level of raf mRNA increased in seven of 10 PB‐induced tumors but in only one of five spontaneous tumors, whereas the level of Ha‐ras mRNA increased in nine of 10 PB‐induced tumors and in four of five spontaneous tumors. The results of our investigation (a) support the hypothesis that hypomethylation of DNA is a nongenotoxic mechanism involved in tumorigenesis, (b) support the notion that PB promotes liver tumors that develop along a pathway different from that leading to spontaneous tumors, and (c) indicate that differences in DNA methylation between C57BL/6 and B6C3F1 mice could, in part, account for the unusually high tendency of the latter strain to develop liver tumors. © 1994 Wiley‐Liss, Inc.
Infrequent p53 mutations in 7,12‐dimethylbenz[a]anthracene–induced mammary tumors in BALB/c and p53 hemizygous mice
Authors: Jerry D. Joseph , Butel Janet S. , Donehower Lawrence A. , Paulson Emily J. , Cochran Charles , Wiseman Roger W. , Medina Daniel 
Published: February 2007

AbstractWe conducted experiments to determine if p53 alterations, which are frequent in human breast cancers, were also common in murine mammary tumors. In 13 mammary tumors from 7,12‐dimethylbenz[a]anthracene (DMBA)‐treated BALB/c mice were immunohistochemically analyzed for overexpression of p53; p53 protein was not detectable. Three of the tumors were established as cell lines in vitro. p53 protein was rarely detected at passage 4 in these lines but was overexpressed by passage 8 in two of them. The p53 nucleotide sequence was shown to be wild type in one primary mammary tumor and in the two p53‐overexpressing cell lines. One cell line that overexpressed p53 in vitro was implanted into BALB/c mice. The resulting tumors retained the wild‐type p53 nucleotide sequence but no longer expressed detectable levels of p53 protein, suggesting that the overexpression of wild‐type p53 was related to in vitro culture conditions. The effect of DMBA on mammary‐tumor development was also tested in mice rendered hemizygous for p53. These mice and wild‐type littermate controls had no differences in susceptibility to induction of mammary tumors by oral administration of DMBA. Furthermore, Southern blot hybridizations detected no gross alterations in the wild‐type p53 allele in mammary tumors from the p53‐deficient mice. Point mutation of the wild‐type p53 allele was also infrequent in the DMBA‐induced mammary tumors from hemizygous p53 mice; it occured in only one of seven tumors. Thus, the p53 gene is apparently not a primary target for genetic alterations in DMBA‐induced mammary tumors. Next, we examined mammary tumors derived from D1 and D2 transplantable hyperplastic alveolar nodule (HAN) outgrowths, which rapidly form tumors containing Ha‐ras mutations after DMBA treatment. As ras and p53 mutants can cooperate in transformation, we examined whether D1 and D2 HAN outgrowths have p53 mutations. Unlike in the DMBA‐induced primary mammary tumors, nuclear p53 accumulation was observed frequently (10 of 14) in tumors that arose from D1 and D2 HAN outgrowths. Direct sequencing of the entire coding region of the p53 cDNA from six D1 and D2 tumors confirmed that the sequence was wild type. Although wild‐type p53 was retained in both DMBA‐induced mammary tumors and mammary tumors derived from D1 and D2 preneoplastic outgrowths, wild‐type p53 overexpression was detected only in D1 and D2 tumors. Therefore, D1 and D2 tumors appear to arise by a pathway in which p53 expression is altered, whereas DMBA induction affects a different pathway that does not require such alteration. © 1994 Wiley‐Liss, Inc.
Inhibition of hepatitis b virus surface antigen gene expression in carcinogen‐induced liver tumors from transgenic mice
Authors: Farza Hend , Dragani Tommaso A. , Metzler Thomas , Manenti Giacomo , Tiollais Pierre , Porta Giuseppe Della , Pourcel Christine 
Published: February 2007

AbstractWe previously showed that hepatitis B surface antigen (HBsAg)‐producing transgenic mice were more sensitive to hepatocarcinogens than their normal littermates were. We have now investigated the regulation of hepatitis B virus (HBV) gene expression in carcinogen‐induced liver tumors of HBV‐carrier transgenic mice and in three cell lines derived from tumor samples. Transcription of the S gene was repressed in 17 tumors even though they had normal levels of liver‐specific mRNAs such as albumin and transferrin. Three hepatoma cell lines, derived from independent tumor samples, were analyzed for their capacity to express the S gene after transfection of cloned DNA. Although they no longer expressed the endogenous S gene, they were still able to express it from transfected viral DNA both transiently and stably. The loss of HBsAg expression in tumors and in the cell lines was accompanied by de novo methylation of the S region, which is a way to permanently repress gene expression. Our data confirm in an animal model previous observations of S‐gene expression in human hepatocarcinoma and suggest a role for its downregulation in tumor progression. © 1994 Wiley‐Liss, Inc.
Characterization of cell lines derived from formaldehyde‐induced nasal tumors in rats
Authors: Bermudez Edilberto , Chen Zhuchu , Gross Elizabeth A. , Walker Cheryl L. , Recio Leslie , Pluta Linda , Morgan Kevin T. 
Published: February 2007

AbstractCell lines derived from formaldehyde‐induced nasal tumors in Fischer 344 rats were established. All of the lines were found to be epithelial and aneuploid and to express keratin, transforming growth factor‐α, and epidermal growth factor receptor transcripts. Two of four lines were tumorigenic upon injection into nude mice, and these lines also contained point mutations in the p53 suppressor gene. The data indicate that these lines possess characteristics that make them a valuable tool for the study of chemically induced respiratory tract carcinogenesis. © 1994 Wiley‐Liss, Inc.
Altered expression of transforming growth factor‐β1 mrna and protein in mouse skin carcinogenesis
Authors: Patamalai Benjamas , Burow David L. , Gimenez‐Conti Irma , Zenklusen Jean Claude , Conti Claudio J. , Klein‐Szanto Andres J. P. , Fischer Susan M. 
Published: February 2007

AbstractTransforming growth factor (TGF)‐β1, whose gene is located on mouse chromosome 7, has been proposed to be involved in skin carcinogenesis. In the study presented here, we demonstrated that single topical treatments with different types of tumor promoters, i.e., the protein kinase C activator 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA, 2 μg); the non–protein kinase C activators anthralin (22.6 μg), benzoyl peroxide (20 mg), and cumene hydroperoxide (1.2 mg); the first‐stage tumor promoters 4‐O‐methyl‐TPA (500 μg) and A23187 (166 μg); and the second‐stage tumor promoter mezerein (2 μg) produced transient induction of TGF‐β1 mRNA in SSIN (inbred SENCAR) mouse skin. The time of maximum induction varied from 3 to 12 h; the relative extent of induction was ranked as cumene hydroperoxide > benzoyl peroxide > anthralin > TPA > 4‐O‐methyl‐TPA > mezerein > A23187. These findings suggested that TGF‐β1 mRNA induction is a common response of skin to several types of complete and stage‐specific promoters; however, the extent of induction did not correlate with the reported hyperplastic activity of single applications of these promoters. We also demonstrated that TGF‐β1 mRNA expression in papillomas of SENCAR mice generally correlated with expression levels of cyclin D1, another gene on chromosome 7, and with stage of tumor progression. TGF‐β1 mRNA expression was constitutively elevated in most squamous cell carcinomas from either initiation‐promotion or complete carcinogenesis protocols. Cell lines established from carcinomas also overexpressed TGF‐β1 mRNA. Immunohistochemical staining of tissue sections of normal and TPA‐treated skin revealed the presence of extracellular TGF‐β1 protein in the dermis and intracellular TGF‐β1 protein in the epidermis, especially in the suprabasal layers. The staining patterns of papillomas varied, with 62 ± 13% of the tissue showing strong intracellular staining but only 25 ± 8% of the connective tissue staining for extracellular TGF‐β1. Variable staining patterns were also found in carcinomas; some areas stained heavily for both the intracellular and extracellular forms of TGF‐β1. Overall, 28 ± 6% of the tissue of the 12 analyzed carcinomas stained for the intracellular form and 18 ± 5% for the extracellular from of TGF‐β1. © 1994 Wiley‐Liss, Inc.
Epidermal expression of transforming growth factor‐α in transgenic mice: Induction of spontaneous and 12‐O‐tetradecanoylphorbol‐13‐acetate‐induced papillomas via a mechanism independent of Ha‐ras activation or overexpression
Authors: Wang Xiao‐Jing , Greenhalgh David A. , Eckhardt Joshua N. , Rothnagel Joseph A. , Roop Dennis R. 
Published: February 2007

AbstractTo assess the requirements for papilloma formation in transgenic mice that over express transforming growth facto‐α (TGF‐α) in the epidermis (HK1.TGFα), we tested the sensitivity of HK1 TGFα mice to tumor promotion with 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) and analyzed the resultant papillomas for synergic c‐Ha‐ras activation and overexpression. We observed that HK1.TGFα mice were highly sensitive to TPA promotion, exhibition multiple papillomas as early as the third week of treatment. After 60 wk of promotion, malignant conversion was not observed and tumors regressed upon removal of the TPA promotion stimulus. Most of the TPA‐induced papillomas did not have detectable c‐Ha‐ras mutations at codons 12, 13, or 61, but three papillomes arising after long‐term TPA promotion (5–7 mo) exhibited c‐Ha‐ras activation at codon 61 (A←T and A←G). Conversely, spontaneous papillomas arising without TPA promotion, including persisting autonomous pipiliomas, were all negative for activating c‐Ha‐ras mutations. Both spontaneous and TPA‐induced HK1.TGFα pipiliomas expressed c‐Ha‐ras message levels similarto those in normal, nontransgenic epidermis or HK1 TGFα nyperpiastic epidermis. These data demonstrate that TGF‐α overexpression can be an initiating event for TPA promotion, that papillomatogenesis in HK1.TGFα mice proceeds frequently via a pathway independent of Ha‐ras activation or overexpression, and, thus, that other events are required for autonomous growth and malignant conversion. © 1994 Wiley‐Liss, Inc.
Infrequent mutation of ha‐ras and p53 in rat mammary carcinomas induced by 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine
Authors: Ushijima Toshikazu , Kakiuchi Hideki , Makino Hiroshi , Hasegawa Ryohei , Ishizaka Yukihito , Hirai Hisamaru , Yazaki Yoshio , Ito Nobuyuki , Sugimura Takashi , Nagao Minako 
Published: February 2007

Abstract2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine(PhlP) is the most abundant of the heterocyclic amines, a group of potent carcinogens contained in cooked meat and fish. Female F344 rats fed a diet containing 100 or 400 ppm PhIP developed mammary carcinomas within 104 or 52 wk, respectively, at the rate of 47% for each group; these carcinomas were examined for mutations in three members of the ras gene family and in the p53 gene. Single‐strand conformation polymorphism (SSCP) analysis and direct sequencing demonstrated a G←A transition at the second position of Ha‐ras codon 12, with the resultant substitution of glutamic acid for glycine, in two of 10 carcinomas induced by 100 ppm PhIP and in one of seven induced by the 400 ppm dose. No mutations in Ki‐ras or N‐ras were detected. cDNA polymerase chain reaction‐SSCP analysis and direct sequencing demonstrated a G←Ttransversion at the third position of p53 codon 130, with the resultant substitution of asparagine for lysine, in one of the 10 carcinomas induced by 100 ppm of PhIP for which freshly frozen samples were available. PhlP‐induced rat mammary carcinogenesis can be regarded as a unique system in that rat mammary carcinomas are negative for ras and p53 mutations. © 1994 Wiley‐Liss, Inc.
Transforming growth factor‐α expression in peritoneal macrophages elicited from SENCAR and B6C3F1 mice: Responses to lipopolysaccharide and 12‐O‐tetradecanoylphorbol‐13‐acetate
Authors: Pfeifer Richard W. , Adams Lorrie A. 
Published: February 2007

AbstractRecent findings in our laboratory indicated that peritoneal macrophages (MPs) elicited from phorbol ester‐sensitive SENCAR mice generated significant amounts of superoxide when stimulated by 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) in vitro; negligible responses were observed for MPs derived from relatively resistant B6C3F1 mice. We hypothesized a similar strain‐dependent secretion of transforming growth factor‐α (TGF‐α) by TPA‐stimulated MPs. TGF‐α secreted by MPs was quantitated by competitive enzyme‐linked immunosorbent assay. After 72 h (maximal secretion), for MPs derived from B6C3F1 mice, in vitro exposure to 10 μg/mL lipopolysaccharide (LPS; non‐lipid‐A‐detoxified) resulted in maximal induction (708 pg/mL), in vivo exposure to intraperitoneally (i.p.) administered TPA (2 μg/mouse) alone resulted in a minimal response (32 pg/mL), and prior in vivo exposure to TPA significantly inhibited (more than 90% suppression) the LPS‐stimulated MP response in culture (i.e., to 62 pg/mL). Although significant amounts of TGF‐α could be detected in both SENCAR‐and B6C3F1‐derived MPs (i.e., approximately 2–3 ng/5x106 cells), SENCAR MPs did not secrete TGF‐α in response to either TPA or LPS. In addition, the use of the semiquantitative reverse transcription‐polymerase chain reaction to detect TGF‐a‐specific mRNA did not support the strain dependency observed for LPS‐stimulated TGF‐α secretion, i.e., detectable transcripts were observed in MP RNA derived from both strains. In conclusion, although TPA itself demonstrated negligible effects on TGF‐α expression in murine MPs, prior in vivo exposure inhibited LPS‐stimulated transcriptional activation and intracellular TGF‐α production. The negligible TGF‐α secretion determined for LPS‐stimulated SENCAR‐derived MPs suggested the possibility of a strain‐specific defect in the posttranslational processing of the proTGF‐α molecule. © 1994 Wiley‐Liss, Inc.
Expression and localization of matrix‐degrading metalloproteinases during colorectal tumorigenesis
Authors: Newell Ken J. , Witty Jean P. , Rodgers William H. , Matrisian Lynn M. 
Published: February 2007

AbstractThe metalloproteinase matrilysin is widely expressed in the epithelial tumor cells of malignant colorectal adenocarcinomas. Approximately 50% of benign adenomas also express low levels of matrilysin that is focally localized. The expression of stromelysin‐1, stromelysin‐3, and gelatinase A was observed in the stromal component of several carcinomas and was not present in adenomatous tissue. The expression of interstitial collage‐nase and gelatinase B was observed in occasional adenomas and carcinomas. Stromelysin‐2 transcripts were not detectable in any of the samples examined. Tissue inhibitor of metalloproteinase‐1 gene expression was widespread and was observed in both epithelial and stromal cells of adenomas and carcinomas. These results indicate that matrilysin gene expression is an early event in colorectal tumorigenesis and that the expression of stromelysin‐1, stromelysin‐3, and gelatinase A is primarily a late event. The observed gene expression patterns suggest that matrilysin may participate in early events in tumor progression and that multiple members of the metalloproteinase family may work in concert to facilitate late‐stage tumor invasion and metastasis. © 1994 Wiley‐Liss, Inc.
A switch from stromal to tumor cell expression of stromelysin‐1 mRNA associated with the conversion of squamous to spindle carcinomas during mouse skin tumor progression
Authors: Wright Jane H. , McDonnell Susan , Portella Giuseppe , Bowden G. Tim , Balmain Allan , Matrisian Lynn M. 
Published: February 2007

AbstractWe previously reported that the expression of stromelysin‐1 (ST‐1), a matrix‐degrading metalloproteinase, correlates with tumor progression in the mouse skin model of carcinogenesis. Using in situ hybridization techniques, we confirmed in this study the expression of ST‐1 mRNA in mouse skin keratinocytes treated with the tumor promoter 12‐O‐tetradecanoylphorbol‐13‐acetate and also observed dramatic expression of ST‐1 message in underlying fibroblastic cells. Benign tumors formed by an initiation/promotion protocol expressed low levels of ST‐1 mRNA, which was localized exclusively to stromal tissue surrounding the tumor cells. Squamous cell carcinomas, produced either by chemical carcinogenesis or by injection of cultured cells derived from chemically initiated squamous cell tumors, expressed high levels of ST‐1 mRNA, which was also localized to adjacent stromal tissues. In contrast, aggressive, highly metastatic spindle cell tumors expressed ST‐1 mRNA in the tumor cells as well as in normal, adjacent stroma. These results suggest that the change from ST‐1 expression in surrounding stromal cells to its expression in the tumor cells themselves is associated with the conversion of squamous to spindle carcinomas and may play a causal role in the ability of these cells to invade and metastasize. © 1994 Wiley‐Liss, Inc.
Increased expression of matrix metalloproteinase‐3 (stromelysin‐1) in cultured fibroblasts and basal cell carcinomas of nevoid basal cell carcinoma syndrome
Authors: Majmudar Gopa , Nelson Bruce R. , Jensen Timothy C. , Johnson Timothy M. 
Published: February 2007

AbstractNevoid basal cell carcinoma syndrome (NBCCS), an autosomal dominant disorder, is characterized by the development of numerous cutaneous basal cell carcinomas (BCCs). To better characterize this disorder, we examined the expression of matrix metalloproteinase‐3 (MMP‐3; also known as stromelysin‐1) in BCC tumor specimens, adjacent normal skin, and fibroblasts isolated from the normal‐appearing skin of NBCCS patients. Three of three BCC tumors obtained from NBCCS patients overexpressed MMP‐3 mRNA. In contrast, only 25% of BCC specimens in patients without NBCCS demonstrated overexpression of MMP‐3 mRNA. Moreover, fibroblasts isolated and cultured from all nine uninvolved skin specimens of NBCCS patients overexpressed MMP‐3 mRNA. MMP‐3 mRNA was not detected or was detected at very low levels in normal skin and fibroblast cultures isolated from normal skin in nonsyndrome patients. ©1994 Wiley‐Liss, Inc.
Ki‐ras mutations in 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone—initiated and butylated hydroxytoluene—promoted lung tumors in A/J mice
Authors: Matzinger Steve A. , Gunning William T. , You Ming , Castonguay Andre 
Published: February 2007

AbstractThe promotional effects of butylated hydroxytoluene (BHT) on lung tumorigenesis induced by 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) was evaluated in a two‐stage model of lung tumorigenesis in the A/J mouse. Mice were treated in two separate experiments with 1.54 mmol/kg (9.1 mg/mouse) NNK, which induced an average of 8.4 and 9.1 tumors/mouse in the experiments. Animals fed a diet that contained 1 g/kg BHT after administration of the carcinogen in these two experiments demonstrated an increase of the tumor multiplicity by 63% and 43%. Multiplicity of forestomach tumors was not effected by BHT in the diet. No differences in lung tumor morphology were seen as a result of the promoting effect of BHT. Mutations in the Ki‐ras oncogene from lung tumors induced by NNK (19 tumors) or by NNK plus a diet containing BHT (34 tumors) were characterized by polymerase chain reaction, single‐strand conformational polymorphism, and direct sequencing. All 19 NNK‐induced tumors not promoted with BHT contained activated Ki‐ras genes with GC→AT transitions at the second base of codon 12. Only 11 of 34 NNK‐induced and BHT‐promoted tumors (32%) had this characteristic Ki‐ras alteration. These data suggest that the NNK‐initiated mouse lung tumorigenesis pathway, which involves the specific mutation of the Ki‐ras oncogene, is altered to a predominantly non‐ras mechanism when these tumors are promoted by BHT in the diet. ©1994 Wiley‐Liss, Inc.