bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infrequent transforming mutations in the transmembrane domain of the neu oncogene in spontaneous rat schwannomas
Authors: Perantoni Alan O. , Turusov Vladimir S. , Buzard Gregory S. , Rice Jerry M. 
Published: February 2007

AbstractEthylnitrosourea (ENU) given transplacentally to rats induces schwannomas of the cranial, spinal, and peripheral nerves, with a high frequency of mutations in the neu proto‐oncogene. To establish the requirement for such mutations in tumorigenesis of the Schwann cell, spontaneous schwannomas from BD‐VI rats were evaluated for transforming mutations in the transmembrane domain of the protein encoded by the neu protooncogene. While all five schwannomas induced transplacentally with ENU were shown to contain T←A transversions in base 2012 of neu by selective oligonucleotide hybridization and dideoxy sequencing of polymerase chain reaction–amplified products from paraffin sections, only one of nine spontaneous schwannomas from untreated rats had the same mutation. Examination of tumors for mutations in codon 12 of Ki‐ras revealed normal alleles. Therefore, the high frequency of mutations in neu in ENU‐induced tumors may be directly attributable to the carcinogen or to the period of development at which exposure occurred, and transforming mutations of the transmembrane domain of neu are not required for tumorigenesis of the Schwann cell. © 1994 Wiley‐Liss, Inc.
A role for myn in Ha‐ras transformation of mouse 10T1/2 fibroblasts
Authors: Taylor William R. , Wright Jim A. 
Published: February 2007

AbstractThe human max protein has been shown to form heterodimers with myc family proteins. The ability of myc+max heterodimers to act as sequence‐specific transcriptional activators appears to be essential for the oncogenic activity of myc. max (also called myn in murine cells) can homodimerize to form a transcriptionally inactive complex. We previously showed that in mouse 10T1/2 cells, a combination of activated ras, c‐myc, and a mutant form of p53 can cooperate in the induction of cellular transformation and metastasis. In the study presented here, we tested the hypothesis that expression of the myn gene may play a role in this cooperative process. Analysis of myn mRNA in these cell lines revealed the presence of a major 2.0‐kb RNA species. This message and the 21‐ and 22‐kDa myn polypeptides it encodes were significantly over expressed in cells transformed by activated ras a lone, by ras in combination with c‐myc or mutant p53, or by ras plus myc plus mutant p53, in comparison with untransformed parental 10T1/2 cells. We also found that induction of ras expression in a cell line harboring an inducible ras gene was accompanied by an increase in myn mRNA expression. Interestingly, cotransfection of 10T1/2 cells with ras and myn inhibited cellular transformation in a focus‐forming assay when compared with transfection with ras alone. These results suggest a role for ras in the regulation of myn gene expression and suggest a model of oncogene cooperativity in which the relative levels of myc and myn gene expression can influence ras transformation of mouse 10T1/2 cells. © 1994 Wiley‐Liss, Inc.
Expression and transcriptional activity of Ap‐1, CRE, and URE binding proteins in B16 mouse melanoma subclones
Authors: Rutberg Susan E. , Goldstein Ira M. , Yang Yang M. , Stackpole Christopher W. , Ronai Zeev 
Published: February 2007

AbstractThe expression and DNA binding activity of members of the activating protein‐1 (AP‐1) and activating transcription factor (ATF) families of transcription factors were analyzed in sham and ultraviolet (UV)‐irradiated subclones of the B16 mouse melanoma cell system. The four subclones we used represent sequential stages in the development and progression of malignant melanoma and exhibit differences in growth and metastatic potential. Western blot analysis revealed differential expression of some AP‐1 (c‐jun, jun‐B, and jun‐D) and ATF (43‐ and 47‐kDa cyclic AMP‐responsive element binding protein (CREB) family members) in the different subclones; while c‐jun expression was noted in the subclones with the greater malignant potential, jun‐D was expressed in those with the lesser malignant potential. Furthermore, a delicate balance between the two forms of CREB was noted; the 47‐kDa CREB appeared, when expressed exclusively, in subclones that exhibit a greater malignant potential. Electrophoretic mobility shift assays using AP‐1, CRE, and UV‐responsive element (URE) consensus sequences indicated that distinct complexes were formed with extracts from each of the four subclones. The complexes were competitively inhibited by each of the target sequences used, suggesting that “cross‐talk”occurs between some AP‐1 and ATF family members in this cell system. Moreover, a multimer of the URE sequence, cloned upstream of a chloramphenicol acetyltransferase reporter gene, was transcriptionally active and responsive to UV irradiation in two of the four subclones. UV‐related transcriptional activation was directly correlated with the expression of a 43‐kDa CREB. Together, these observations identify members of AP‐1 and CREB families whose expression and activities correlate with the malignant potential of subclones that represent different stages in melanoma development and progression. © 1994 Wiley‐Liss, Inc.
Positive and negative regulations of albumin gene expression by retinoids in human hepatoma cell lines
Authors: Yamada Yasuhiro , Shidoji Yoshihiro , Fukutomi Yasushi , Ishikawa Takashi , Kaneko Takashi , Nakagama Hitoshi , Imawari Michio , Moriwaki Hisataka , Muto Yasutoshi 
Published: February 2007

AbstractAll‐trans‐3, 7, 11, 15‐tetramethyl‐2, 4, 6, 10, 14‐hexadecapentaenoic acid (designated “acyclic retinoid”) induced upregulation of the albumin gene expression at its transcriptional level, whereas all‐trans‐retinoic acid (RA) induced downregulation of the expression in both PLC/PKF/5 and HuH7 human hepatoma cell lines. These up and downregulations of the albumin gene expression coordinated with high and low levels of mRNA for hepatocyte nuclear factor‐1 (HNF‐1), which is one of the most potent transcription factors for the albumin gene, implying that retinoids may regulate albumin gene expression through HNF‐1 expression in opposite ways. The PLC/PRF/5 and HuH7 hepatoma cell lines expressed retinoid × receptor‐α (RXRα) mRNA, whose expression was constitutive. Acyclic retinoid and all‐trans‐RA both induced upregulation of retinoic acid receptor‐β (RARβ), and both suppressed cell proliferation‐related phenotypic expressions by the α‐fetoprotein gene and the c‐myc oncogene. 9‐cis‐RA, whose receptor is known to be RXRα, also induced upregulation of albumin and HNF‐1 expression. These results suggest that acyclic retinoid may act through both RXRα and RARβ, whereas all‐trans‐RA conveys only RARβ‐mediated functions, at least in these two hepatoma cell lines. © 1994 Wiley‐Liss, Inc.
The role of 12 cDNA‐expressed human, rodent, and rabbit cytochromes P450 in the metabolism of benzo[a]pyrene and benzo[a]pyrene trans‐7, 8‐dihydrodiol
Authors: Shou Magang , Korzekwa Kenneth R. , Crespi Charles L , Gonzalez Frank J. , Gelboin Harry V. 
Published: February 2007

AbstractThe potent carcinogen benzo[a]pyrene (B[a]P) and its metabolite B[a]P trans‐7, 8‐dihydrodiol (7, 8‐diol) require metabolic activation by the microsomal cytochrome P450s (P450s) to exert several adverse biological effects, including binding to DNA, toxicity, mutagenicity, and carcinogenicity. In the study reported here, we defined the role of each of 12 individual cDNA‐expressed cytochrome P450s in the metabolism of B[a]P and 7, 8‐diol. Human P450s 1A1 and 1A2 were expressed in the absence or presence of epoxide hydrolase (EH) in a human lymphoblastoid cell line, and six human and five rodent and rabbit P450s were expressed from cDNA with vaccinia virus vectors in the hepatoma cell line Hep G2. B[a]P metabolism resulted in nine metabolites (three diols, three quinones, and three phenols), which were separated, identified, and quantitated by high‐pressure liquid chromatography. In the human lymphoblastoid cells, human 1A1 metabolized B[a]P at a rate 4.5 times greater than that for 1A2. EH was shown to be directly involved in B[a]P activation, since increasing the amount of EH resulted in less 7‐hydroxybenzo[a]pyrene and more 7, 8‐diol formation. Of the human P450s expressed with the vaccinia virus vectors in Hep G2 cells, 1A2 and 2C9 showed the highest activity and 2B6 showed moderate activity for B[a]P metabolism. Mouse 1A1 had activity 40 times higher than any human, rabbit, or rodent P450s, indicating the potential pitfalls of extrapolating P450 activity across species. Metabolism of the 7, 8‐diol resulted in six metabolites (four tetrols and two triols). In the lymphoblastoid cells, human 1A1 was shown to be 4.2 times more active than 1A2 for 7, 8‐diol metabolism. Among human P450s expressed from vaccinia virus, 1A2, 2E1, and 2C9 gave the highest activity, and 2C8 and 3A4 showed moderate activity for 7, 8‐diol metabolism to the diol epoxides. Again, mouse 1A1 was much more active than any other P450. These studies, in which we determined the capacity of individual P450 in the metabolism and activation of B[a]P and 7, 8‐diol, may thus lead to a better understanding of how P450s control the detoxification and activation of polycyclic aromatic hydrocarbons. © 1994 Wiley‐Liss, Inc.
Ultraviolet b light‐induced mutagenesis of p53 hotspot codons 248 and 249 in human skin fibroblasts
Authors: Amstad Paul , Hussain S. Perwez , Cerutti Peter 
Published: February 2007

AbstractMutations in the p53 tumor suppressor gene are detected in approximately half of non‐melanoma skin cancers. The type of base‐pair changes observed strongly suggests solar radiation as the causative mutagen. Mutations are distributed nonrandomly and form moderate hotspots. We studied the capacity of ultraviolet B light (UVB, 280–320 nm) to induce base‐pair changes into the p53 exon 7 sequence extending from nt 14067 to 14075 in human skin fibroblasts. This sequence contains hotspot codon 248. UVB induced mostly C←A and G←T transversions. The base‐pair change with the highest relative abundance was C←A in the first position of codon 250 (CCC←ACC), followed by (in diminishing relative abundance) G←T in the third position of codon 249 (AGG←AG1), C←A in the first position of codon 248 (CGG←AGG), and C←A in the third position of codon 247 (AAC←AAA). The C←T transition in the third position of codon 247 (AAC←AAT) occurred with moderate efficiency. These base‐pair changes are compatible with pyrimidine photodimers as premutagenic lesions, but they could also form opposite 8‐hydroxyguanine, which is the major oxidation product of guanine. No evidence was obtained for the presence of tandem double CC←TT transitions in the untranscribed strand at codons 247/248 and 250. The relative abundance of mutations induced by UVB in the p53 sequence extending from codon 247 to 250 in human fibroblasts does not correlate with mutations observed in the DNA from non‐melanoma skin cancer. This lack of correlation suggests that the mutability of this p53 sequence at the DNA level plays only a minor role in the pathogenesis of non‐melanoma skin cancer in humans. © 1994 Wiley‐Liss, Inc.
Similar patterns of hypomethylation in the β‐hydroxy‐β‐methylglutaryl coenzyme a reductase gene in hepatic nodules induced by different carcinogens
Authors: Rossiello Maria Rosaria , Rao Prema M. , Rajalakshmi Srinivasan , Sarma Dittakavi S. R. 
Published: February 2007

AbstractOur earlier studies demonstrated that the β‐hydroxy‐β‐methylglutaryl coenzyme A (HMG CoA) reductase gene is hypomethylated and overexpressed in hepatic nodules initiated by 1,2‐dimethylhydrazine (1,2‐DMH). The study presented here examined whether the pattern of DNA methylation of the HMG CoA reductase gene in hepatic nodules reflected carcinogen‐DNA interaction during initiation. Accordingly, hepatic nodules were generated in male Fischer 344 rats with either 1,2‐DMH or aristolochic acid (AA), which interact predominantly with the guanine and adenine bases in DNA, respectively. DNA from individual nodules was restricted with Hpall, Mspl, and Hhal, and the fragments obtained were hybridized to a cDNA probe for HMG CoA reductase. The results indicated that the hypomethylation pattern in the reductase gene in the nodules initiated with these two carcinogens was similar, although they interacted with different bases in the DNA. The question still remained whether the DNA fragments obtained by digesting the two sets of nodules with the restriction endonucleases were from the same domains in the genome of HMG CoA reductase. To examine this, probes for the different domains of the HMG CoA reductase gene were generated from the cDNA using the restriction enzyme Accl. Three probes were obtained: (i) a 5′‐end fragment corresponding to the membrane‐spanning region, (ii) a second fragment corresponding to the 3′‐end of the protein, and (iii) a third fragment spanning the region between (i) and (ii). Each of these probes was radiolabeled and hybridized to the Hpall‐and Hhal‐generated fragments from the DNA of hepatic nodules initiated with 1,2‐DMH and AA. Irrespective of the carcinogen used for initiation, hypomethylation occurred in all three domains of the gene. More important, the pattern of hypomethylation was similar in the nodules initiated by the two carcinogens. Furthermore, an overall similarity was seen in the hypomethylation patterns in the c‐myc and c‐Ha‐ras genes in the DNA of nodules initiated with either 1,2‐DMH or AA. These results raise the possibility that the pattern of hypomethylation established in the hepatic nodules may not directly reflect the interaction between the initiating carcinogen and DNA but may represent a unique phenotype of hepatic nodules. © 1994 Wiley‐Liss, Inc.
Clonal variation of tumorigenic potential in v‐Ha‐ras‐transformed human bronchial epithelial cells: Relationship to ras oncogene expression and CAD gene amplification
Authors: Forrester Kathleen , Kispert Jennifer , Sanchez Janet H. , Gerwin Brenda I. , Tlsty Thea D. , Harris Curtis C. 
Published: February 2007

AbstractInfection of an SV40 large‐T antigen‐“immortalized” human bronchial epithelial cell line with a Zip‐v‐Ha‐ras retroviral vector resulted in a mass culture that was tumorigenic in athymic nude mice. A tumor cell line derived from passage of the mass culture in vivo, however, exhibited increased tumorigenicity and v‐Ha‐ras expression. To examine and compare the molecular events involving the ras oncogene during cell transformation in vitro and subsequent tumor formation in vivo, clonal cell populations were isolated from the v‐Ha‐ras‐transformed mass culture. While the clonal cell lines exhibited diverse tumorigenic profiles, these differences did not correlate with v‐Ha‐ras expression. However, the expression of the activated ras gene, while not necessary for growth in vitro, did appear to be associated with a selective growth advantage in vivo. In addition, the modulation of gene amplification ability in these cells was not associated with the induction of tumorigenicity or v‐Ha‐ras expression. ©1994 Wiley‐Liss, Inc.
Far less frequent mutations in ras genes than in the p53 gene in skin tumors of xeroderma pigmentosum patients
Authors: Sato Mayumi , Nishigori Chikako , Lu Yanjun , Zghal Mohamed , Yagi Takashi , Takebe Hiraku 
Published: February 2007

AbstractMutations in Ha‐ras, and n‐rasNras genes in squamous and basal cell carcinomas in patients with xeroderma Pigmentosum (XP) were examined by the polymerase chain reaction followed by single‐strand conformation polymorphism analysis and direct base sequencing. No mutation was detected in codons 12, 13, and 61 of the ras genes in XP skin tumors. This was in contrast with previous findings of a high frequency of mutation in the p53 gene in skin tumors in XP patients. A novel mutation in codon 6 of the ki‐ras gene was detected in a squamous cell carcinoma. The mutation was a C→T transtion at a dipyrimidine (5′‐CT) sequence and could have been produced by solar ultraviolet light. The mutated ras gene did not have the ability to transform NIH/3T3 cells. In three tumors, multiple base substitutions were detected in exon 1 of the Ki‐ras and N‐ras genes. These results and our previous work on p53 gene mutations suggest that mutations in ras genes are far less frequent than in the p53 gene in the skin tumors in XP patients and that ras genes are less important in skin tumorigenesis in XP patients that is the p53 gene.
Differential cytotoxicity in mouse epidermal JB6 cells: A potential mechanism for oxidant tumor promotion
Authors: Jain Pramod T. , Chang Seung H. , Berezesky Irene K. , Amstad Paul , Cerutti Peter A. , Trump Benjamin F. 
Published: February 2007

AbstractIt has been suggested that superior antioxidant defense systems protect promotion‐sensitive (p + t) mouse epidermal JB6 clone 41 cells from excessive deleterious effects of oxidants, allowing their clonal expansion in contrast to that of promotion‐resistant (p—) clone 30 cells. In support of this concept, we report that oxidants produced by xanthine/xanthine oxidase cause more cytotoxicity, cellular damage, and cell death in p—cells. Cell surface blebbing, an early morphological consequence of oxidative injury, was detected in cultures grown on glass coverslips. While a rise in cytosolic ionized calcium ([Ca2+]i) preceding bleb formation was observed in both p+ and p— cells by digital imaging fluorescence microscopy, elevated levels of [Ca2+]i were sustained longer in p— cells. This increase was dependent on the levels of extracellular ionized calcium ([Ca2+]e) in p+ but not p— cells. We conclude that the superior antioxidant defense or improved Ca2+ buffering of promotable clone 41 cells protects them from more severe deregulation of [Ca2+]i and, as a consequence, from excessive cytotoxicity after exposure to oxidant promoters. ©1994 Wiley‐Liss, Inc.
Cloning of the syrian hamster p53 gene: Structural and functional characterization of the upstream promoter region
Authors: Albor Amador , Laborda Jorge , Notario Vicente 
Published: February 2007

AbstractWe isolated the p53 gene from Syrian hamster embryo cells by cosmid cloning procedures. The organization of the hamster p53 gene was similar to that of other mammalian p53 genes; it had 11 exons, a noncoding exon 1, and a long intron 1 (about 6.5 kb). The upstream p53 promoter was isolated, and the nucleotide sequence of a region encompassing 694 bp upstream from the exon/intron 1 boundary plus the first 6 nt of intron 1 was determined. This genomic region was highly homologous to those of mice and humans but contained a repetitive element not present in either species. Sequence comparisons with the murine and human promoters revealed the presence of similar transcription‐factor binding motifs mapping within a 431‐bp Sacl‐Pstl fragment. Transient transfection assays of primary Syrian hamster embryo cells and neoplastic cell lines with recombinant constructs in which the Sacl‐Pstl fragment was placed upstream of a bacterial chloramphenicol acetyltransferase (CAT) gene revealed the efficient expression of CAT activity. Primer extension analyses identified several putative transcription initiation sites within the p53 upstream promoter, the strongest of which was located 315 bp upstream from the exon/intron 1 junction and about 30 bp upstream from the region encompassing the regulatory motifs. ©1994 Wiley‐Liss, Inc.
Expression of multiple isoforms of protein kinase C in normal human colon mucosa and colon tumors and decreased levels of protein kinase C β and η mRNAs in the tumors
Authors: Doi Sadyuki , Goldstein Cebra , Hug Hubert , Weinstein I. Bernard 
Published: February 2007

AbstractPrevious studies have suggested that protein kinase C (PKC) may play an important role in colon carcinogenesis and that human colon tumors have less total PKC enzyme activity than normal tissue. Because PKC is a multigene family that enocodes for at least 11 distinct isofroms, in the study reported here we analyzed the expression of six of these isoforms at the mRNA level by northern blot hybridization in 22 pairs of primary colon tumors (of various stages), and adjacent normal mucosa samples. We found that the normal mucosa samples expressed the mRNA of the following isoforms of PKC, in decreasing order of abundance: PKCδ>PKC>PKCα>PKCβ>PKCϵ. There was no consistent difference in the levels of PKCα, PKCδ, and PKCη. mRNAs between the normal mucosa and the tumor samples. PKCγ was expressed at a very low level in two of the colon tumors but could not be detected in the remaining tumors of any of the normal mucosa samples. The levels of both PKCβ and PKCη mRNAs were singificantly lower in the tumor samples than in the normal mucosa samples, and this was true of adenomas as well as Dukes' stage A, B, and Cadenocarcinomas. Furthermore, the devrease in PKCη mRNA appeared to be greater in the more poorly differentiated carcinomas. This finding in of interest becouse PKCη is normally expresed in the more differentiated cells of epithelial tissues. The devreased levels of both PKCβ and PKCη mRNAs ocurred early in the multistage process of colon carcinogenesis, as it was also seen in adenomas. The functional significane of these changes remains to be determined.
A p53 mutation in exon 5 associated with adenovirus transformation
Authors: Eyler Yvonne L. , Siwarski David F. , Huppi Konrad E. , Lewis Andrew M. 
Published: February 2007

AbstractThe adenovirus type 5 (Ad5) 55‐kDa E1B oncoprotein has been shown to form complexes with the p53 tumor suppressor protein. These complexes are thought to interfere with normal p53 activity and may be responsible for the paucity of p53 mutations in cells transformed by these viruses. This report describes an example of a p53 mutation in exon 5 in an Ad5‐transformed cell line that exhibited less expression of E1B 55‐kDa protein and a longer tumor‐latency phenotype than another Ad5‐transformed cell line expressing wild‐type p53. The finding of a p53 mutation in an Ad5‐transformed cell line is unusual, especially considering the current theory that p53‐E1B interactions play an important role in adenovirus transformation. This mutation could represent an alternative method of inactivating p53 function in the absence of sufficient levels of E1B 55‐kDa oncoprotein. © 1995 Wiley‐Liss Inc.
Mutation, loss of heterozygosity, and recombination of the p53 gene in mouse forestomach tumors induced by 2‐amino‐3,4‐dimethylimidazo[4,5‐f]quinoline
Authors: Ushijima Toshikazu , Makino Hiroshi , Okonogi Hideo , Hosoya Yoko , Sugimura Takashi , Nagao Minako 
Published: February 2007

Abstract2‐Amino‐3,4‐dimethylimidazo[4,5‐f]quinoline (MelQ), a food mutagen, induces forestomach tumors in CDF1 mice. We established a polymerase chain reaction (PCR)–single‐strand conformation polymorphism (SSCP) analysis system to detect mutations in the mouse p53 gene exons 2–10, which encompass all five regions conserved among species, and a system to examine loss of heterozygosity (LOH) that uses newly identified polymorphisms between BALB/c and DBA mice, the parental strains of CDF1 mice. Four original forestomach tumors (one papilloma, two carcinomas, and one lymph‐node metastasis) and four cell lines derived from four independent forestomach tumors were examined with the PCR‐SSCP system and by polymorphism analysis. Of the four original tumors, the papilloma had a G→A transition at the second position of codon 171, and one carcinoma had a G→T transversion at the second position of condon 113 with loss of the wild‐type allele, whereas the other two carcinomas had no detectable mutations. Of the four cell lines, two had a base substitution and LOH, and the other two had double mutations (a base substitution and a deletion). By amplification of the double mutations in a fragment, the two cell lines were shown to have four kinds of alleles, indicating induction of recombination within the p53 gene. Our results show that our PCR‐SSCP analysis system is efficient for detecting p53 mutations in mouse genomic DNA and that alteration of the p53 gene plays a significant role in MelQ‐induced mouse forestomach carcinogenesis. © 1995 Wiley‐Liss Inc.