bluuebunny/crossref_metadata_2025_split huggingface dataset:
A revised map position for the Ha‐ras gene on mouse chromosome 7: Implications for analysis of genetic alterations in rodent tumors
Authors: Kemp Christopher J. , Bremner Rod , Balmain Allan 
Published: February 2007

AbstractThe mouse Ha‐ras gene has previously been mapped to the central region of chromosome 7, 31 cM from the centromere, using an interspecific Mus musculus/Mus spretus backcross (Saunders AM, Seldin MF, Genomics 8:525–535, 1990). However, analysis of mitotic recombinations in mouse skin tumors from intraspecific F1 hybrid mice suggested a more distal location for the Ha‐ras gene on chromosome 7 (Bremner R, Balmain A, Cell 61:407–417, 1990). In the study reported here, we demonstrated, by analysis of Ha‐ras gene mutations in skin tumors from interspecific M. spretus/M. musculus F1 hybrids, the existence only in M. spretus of a pseudogene or other Ha‐ras—related sequence that is probably the sequence originally mapped by Saunders and Seldin. The functional Ha‐ras gene maps to the distal region of chromosome 7, and it is this sequence that acquires mutations in chemically induced tumors.
Genetic predisposition and mesenchymal‐epithelial interactions in ras + myc—induced carcinogenesis in reconstituted mouse prostate
Authors: Thompson Timothy C. , Timme Terry L. , Kadmon Dov , Park Sang H. , Egawa Shin , Yoshida Kazunari 
Published: February 2007

AbstractUsing a mouse prostate reconstitution (MPR) model system, strain‐specific responses to the ras and myc oncogenes were investigated. When ras + myc were introduced into both the mesenchymal and epithelial compartments of the urogenital sinus, poorly differentiated prostate cancer was produced at a high frequency (>90%) in inbred C57BL/6 mice. In contrast, under similar conditions, inbred BALB/c MPRs formed benign prostatic hyperplasia that converted to cancer at a low frequency (<10%). Restricting the oncogenes to the mesenchymal or epithelial compartments revealed that oncogene activities were more pronounced in the mesenchyme of C57BL/6 mice and resulted in elevated transforming growth factor‐β1 expression along with a severe desmoplastic reaction. Heterologous MPRs composed of BALB/c mesenchyme and C57BL/6 epithelium or vice versa demonstrated that intrinsic properties of BALB/c mesenchyme can arrest the progression of ras + myc—initiated C57BL/6 epithelium from benign hyperplasia to malignant carcinoma.
Interleukin‐1α gene expression and localization of interleukin‐1α protein during tumor promotion
Authors: Oberyszyn Tatiana M. , Sabourin Carol L. K. , Bijur Gautam N. , Oberyszyn Andrew S. , Boros Laszlo G. , Robertson Fredika M. 
Published: February 2007

AbstractTreatment of the dorsal epidermis of SENCAR mice with 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) induced a time‐ and dose‐dependent stimulation of interleukin‐1α (IL‐1α) gene expression. Levels of IL‐1α mRNA were elevated as early as 15 min and peaked at 3–4 h after a single application of TPA (2 μg or 10 μg). IL‐1α gene expression increased in epidermal tissue isolated from SENCAR mice at 1, 3, 6, 10, 16, and 22 wk after a single treatment with 10 nmol 7,12‐dimethylbenz[a]anthracene (DMBA) and subsequent twice‐weekly application of 2 μg TPA. IL‐1α‐immunoreactive protein was specifically localized within suprabasal keratinocytes in cutaneous tissue isolated from mice treated with DMBA‐TPA for 1–22 wk and in nonproliferating cells located within papilloma tissue isolated from SENCAR mice at 22 wk after initiation and promotion. Basal cells within hyperplastic epidermis did not produce IL‐1α‐immunoreactive protein. DMBA treatment alone did not induce IL‐1α gene expression. Injection of IL‐1α‐specific antibodies (50 μg) into SENCAR mice via the tail vein 2 h before treatment with TPA (2 μg or 10 μg) significantly (P < 0.05) inhibited the skin thickening usually observed 24 h after treatment with TPA. Autoradiography studies showed that injection of anti—IL‐1α antibodies inhibited incorporation of [methyl‐3H]thymidine by keratinocytes within the epidermis and by cells within hair follicles. It also inhibited neutrophil infiltration into the dermis, which usually results from topical application of TPA. These data suggest that IL‐1α is a pivotal cytokine produced by specific subpopulations of epidermal keratinocytes and that IL‐1α primarily regulates the epidermal proliferative response of a distinctly separate population of keratinocytes after topical exposure of murine epidermis to TPA and secondarily modulates neutrophil migration into the dermis. Consequently, manipulation of IL‐1α may be a way to attenuate or abrogate the cutaneous response to TPA by altering keratinocyte proliferation, the resultant hyperplasia, and a portion of the inflammatory response characterized by dermal infiltration of neutrophils.
Activation of immediate‐early gene expression by peroxisome proliferators in vitro
Authors: Ledwith Brian J. , Manam Sujata , Troilo Philip , Galloway Sheila M. , Nichols Warren W. , Joslyn Dennis J. 
Published: February 2007

AbstractThe hepatocarcinogenicity of peroxisome proliferators (PPs) in rodents has been attributed both to oxidative DNA damage resulting from excessive leakage of peroxisomal H2O2 and to increased hepatocellular replication that may be independent of peroxisome proliferation. Because of the growing association between tumor promotion and alterations in growth‐regulatory signal transduction pathways, we investigated whether PPs can modulate these pathways in a mouse liver epithelial cell line, BNL‐CL.2. We tested two PPs that differ markedly in rodent tumorigenicity for their ability to activate immediate‐early proto‐oncogene expression. 4‐Chloro‐6‐(2,3‐xylidino)‐2‐pyrimidinylthioacetic acid (Wy‐14643), a highly tumorigenic PP, was an exceptionally strong inducer of c‐fos expression. In contrast, diethylhexyl phthalate (DEHP), a weakly tumorigenic PP, was a very poor inducer of c‐fos expression. Wy‐14643 was also stronger than DEHP in stimulating c‐jun expression, whereas both PPs were fairly strong inducers of jun‐B and jun‐D. The induction of fos and jun expression by Wy‐14643 was specifically inhibited by the protein kinase C inhibitor 1‐(5‐isoquinolinesulfonyl)‐2‐methylpiperizine dihydrochloride (H‐7). DEHP‐induced gene expression was strongly inhibited by H‐7, but was also partially inhibited by an inhibitor of protein kinase A. The activation of fos and jun gene expression by PPs was independent of peroxisome proliferation since it was an immediately‐early response not requiring protein synthesis and since the cell lines used in this study do not undergo peroxisome proliferation. Our results raise the possibility that the carcinogenicity of PPs may be due, in part, to epigenetic modulation of growth‐regulatory signal transduction pathways. © 1993 Wiley‐Liss, Inc.
Mutations of the p53 tumor suppressor gene in neoplasms of the human nervous system
Authors: Ohgaki Hiroko , Eibl Robert H. , Reichel Martin B. , Mariani Luigi , Petersen Iver , Höll Thomas , Wiestler Otmar D. , Kleihues Paul , Schwab Manfred , Gehring Manuela 
Published: February 2007

AbstractA variety of neoplasms of the human nervous system were analyzed for the presence of mutations in the p53 tumor suppressor gene. DNA was extracted from frozen or formalin‐fixed, paraffin‐embedded material. Single‐strand conformation polymorphism (SSCP) analysis for exons 5–8 was followed by direct DNA sequencing. Mutations leading to an amino acid change were found in three of 11 (27%) low‐grade (World Health Organization (WHO) Grade II) astrocytomas. They were located in codon 183 (TCA → TGA) of exon 5, codon 237 (ATG → ATA) of exon 7, and codon 273 (CGT → CAT) of exon 8. In one of these cases, the sequence indicated loss of the wild‐type allele. Of 12 juvenile pilocytic astrocytomas (WHO Grade I), none contained a p53 mutation, suggesting a different molecular basis for this childhood neoplasm. Except for a mutation in one of seven (14%) meningeal hemangiopericytomas (codon 238; TGT → TTT, Cys → Phe), no mutations were observed in exons 5–8 of the p53 gene in any of the following tumors of the nervous system and its coverings: 13 schwannomas, 12 central neurocytomas, 22 meningiomas, 10 choroid plexus papillomas and carcinomas, and 30 neuroblastomas of the sympathetic nervous system. These and published data support the view that p53 mutations are frequently involved both in low‐grade and progressive (anaplastic) astrocytomas, including glioblastomas multiforme. Oligodendrogliomas, medulloblastomas, meningiomas, and hemangiopericytomas rarely (<15%) show p53 mutations in exons 5–8, whereas none of the remaining nervous system neoplasms revealed evidence of an involvement of the p53 gene in their development.
Ki‐ras oncogene mutations in tumors and DNA adducts formed by benz[j]aceanthrylene and benzo[a]pyrene in the lungs of strain A/J mice
Authors: Mass Marc J. , Ross Jeffrey A. , Nesnow Stephen , Jeffers Anita J. , Nelson Garret , Galati Anthony J. , Stoner Gary D. 
Published: February 2007

AbstractStrain A/J mice received intraperitoneal injections of benz[j]aceanthrylene (B[j]A) or benzo[a]pyrene (B[a]P). At 24, 48, and 72 h, lung tissues were removed for analysis of B[a]P‐ or B[j]A‐derived DNA adduct formation during the first 3 d of exposure. One group of mice exposed to these hydrocarbons was kept for 8 mo to determine lung tumor multiplicity, the occurrence of mutations in codons 12 and 61 of the Ki‐ras gene in the tumors that arose, the relationship between Ki‐ras oncogene mutations in tumors, and the presence and quantity of genomic DNA adducts. The major DNA adduct in the lungs of mice exposed to B[a]P was N2‐(10β‐[ + B,7α, 9α‐trihydroxy‐7,8,9,10‐tetrahydrobenzo[a]pyrene]yl)‐deoxyguanosine (BPDE‐l‐dGuo) arising from bay‐region diolepoxide activation of B[a]P and was consistent with the occurrence of tumors with mutations GGT → TGT (56%), GGT → GTT (25%), and GGT → GAT (19%) in codon 12, all involving mutations of a guanine. B[j]A, a demethylated analogue of 3‐methylcholanthrene (3‐MCA) with an unsaturated cyclopenta ring, produced 16‐ to 60‐fold more tumors at equivalent doses than did B[a]P; the mutations in tumors were GGT → TGT (4%), GGT → GTT (30%), and GGT → CGT (65%). Analysis of adduction patterns in DNA suggested that B[j]A was activated to form DNA‐binding derivatives in A/J mouse lungs primarily at the cyclopenta ring even though B[j]A contains a bay region. As reported in the published literature, the mutation spectrum induced by 3‐MCA in Ki‐ras codon 12 of mouse cells is similar to that of B[a]P but not to that of its close relative B[j]A. In contrast to B[j]A, 3‐MCA is activated mostly via a bay‐region diol‐epoxide since its cyclopenta ring is saturated and not easily epoxidated. Therefore, we propose that the GGT → CGT mutations produced by B[j]A in Ki‐ras codon 12 were mostly the result of cyclopentaring‐derived adducts.
Ki‐ras mRNA regulation in untransformed mouse lung cells
Authors: Li Jia , Beer David G. 
Published: February 2007

AbstractAlthough the Ki‐ras gene is an often‐observed transforming gene in lung tumors, little is understood of the factors that regulate the expression of the normal gene in lung cells. Therefore, we used untransformed mouse lung epithelial cells to determine the effect of serum, growth factors, and cell confluence on the regulation of Ki‐ras mRNA expression. In subconfluent cells synchronized by 24‐h serum deprivation, the refeeding of media containing serum resulted in the expression of both Ki‐ras and H4 histone mRNA. No change in the expression of either gene was observed in cells refed with media alone. In confluent cell cultures, the refeeding of media with serum had no effect on the expression of these genes, suggesting that cell‐density—dependent mechanisms can override the serum‐induced stimuli for Ki‐ras and H4 histone mRNA expression. Confluent cells expressed low but detectable Ki‐ras mRNA levels consistent with constitutive expression of this gene independent of its role in mitogenic stimuli. EGF (10 ng/mL) and TGF‐α (10 ng/mL) were found to induce transient increases in Ki‐ras mRNA but large increases in H4 histone mRNA levels. Similarly, 48‐h‐conditioned media obtained from two transformed mouse lung cells containing activated Ki‐ras genes and overexpressing Ki‐ras mRNA were observed to increase both Ki‐ras and H4 histone mRNA in the untransformed mouse lung cells. The expression of these genes in mouse lung cells therefore appeared to be linked to stimuli provided by specific growth factors as well as by autocrine factors elaborated by lung tumor cells. The studies reported here provide insight into the regulation of the Ki‐ras mRNA in untransformed lung cells and the factors that may contribute to the elevated levels of Ki‐ras mRNA often observed in transformed lung cells.
ras mutations in 2‐amino‐3‐methylimidazo‐[4,5‐f]quinoline—induced tumors in the CDF1 mouse
Authors: Herzog Christopher R. , Schut Herman A. J. , You Ming , Maronpot Robert R. 
Published: February 2007

Abstract2‐Amino‐3‐methylimidazo[4,5‐f]quinoline (IQ) is a very potent mutagen that is carcinogenic in rodents and nonhuman primates. IQ‐induced CDF1 mouse lung and liver tumors were examined for activated Ki‐ras and Ha‐ras genes, respectively. Polymerase chain reaction (PCR)—amplified target DNAs were analyzed for mutations of codons 12, 13, and 61 by single‐strand conformation polymorphism (SSCP) and direct sequencing methods. All mutations were localized to codon 61 of the ras genes. Forty‐nine of 54 lung tumors induced by IQ possessed activating Ki‐ras mutations, as did 20 of 26 lung tumors from the vehicle‐treated animals; 80% and 75% of these mutations, respectively, were A → T transversions of the second nucleotide redundant. One lung adenoma from the IQ‐treated group contained a tandem duplication of the sequence corresponding to codons 50–57 of the Ki‐ras gene (unpublished observations). In addition, seven of 34 IQ‐induced liver tumors harbored activating Ha‐ras mutations: five were C → A (G → T) transversions at the first nucleotide, and two were A → T transversions at the second nucleotide of codon 61. None of the 15 liver tumors collected from the vehicle‐treated mice possessed Ha‐ras mutations in codon 12, 13, or 61. These data indicate that IQ induces Ha‐ras gene activation in CDF1 mouse liver tumors. The mechanism of lung tumor induction by IQ, however, is obscured by the high frequency of Ki‐ras A → T mutations observed in both the IQ‐induced and spontaneous lung tumors. The different ras mutational spectra in lung and liver tumors may suggest either that two different pathways of IQ metabolism exist in these organs or that IQ contributes to CDF1 lung tumorigenesis by a mechanism other than its direct interaction with the Ki‐ras gene.
Dependence of induction of osteocalcin gene expression on the presence of wild‐type p53 in a murine osteosarcoma cell line
Authors: Chandar Nalini , Campbell Phil , Novak Josef , Smith Martin , Smith Martin 
Published: February 2007

AbstractThe p53 gene undergoes rearrangement in a high percentage of osteosarcomas, resulting in loss of its expression. A p53‐null murine osteosarcoma cell line F6 was transfected with either a wild‐type or a mutant p53 gene. Stably transfected cell lines were obtained, and their differentiation capabilities were compared in vitro with the parental cell line. Alkaline phosphatase and osteocalcin expression were measured as early and late differentiation markers, respectively. Induction of alkaline phosphatase expression was not affected by the presence of either p53 gene, whereas osteocalcin expression was seen in cells containing the wild‐type p53 gene but not in the parental p53‐null or mutant‐expressing cell lines. That the induction of osteocalcin was intrinsically dependent on the presence of wild‐type p53 was also indicated by the use of a temperature‐sensitive Val 135 p53 mutant at 32°C; predominant expression of p53 in the wild‐type conformation resulted in osteocalcin expression. While the wild‐type p53 gene could suppress tumor formation in vivo, the tumors expressing the mutant p53 gene grew two to three times as large as the tumors that did not express p53. Therefore, the absence of end‐point differentiation in bone due to p53 rearrangements may contribute to the maintenance of the tumorigenic phenotype in osteosarcomas.
Mutations of the p53 tumor suppressor gene and the ras gene family in intrahepatic cholangiocellular carcinomas in Japan and Thailand
Authors: Kiba Takayoshi , Tsuda Hitoshi , Hirohashi Setsuo , Inoue Shuji , Sugimura Takashi , Pairojkul Chawalit 
Published: February 2007

AbstractThe incidence and pattern of mutations of the ras oncogenes and the p53 tumor suppressor gene have been shown to differ among different cancer types and even among the same cancer types with different etiological backgrounds. For example, in a previous study we showed that not only the etiology but also the incidence of point mutation of the c‐Ki‐ras oncogene in cholangiocellular carcinomas (CCCs) differ between Japanese and Thai patients. In the study presented here, we examined the incidence of mutations in the ras gene family and the p53 gene in CCCs of both Japanese and Thai patients by single‐strand conformation polymorphism and direct sequencing analyses and compared the pattern of p53 mutation between these two CCC groups. Although the incidence of ras mutation differed markedly between Japanese (seven of 12, 58%) and Thai (two of 26, 8%) cases, the incidence of p53 mutation was similar: four of 12 (33%) and nine of 26 (35%), respectively. Except for one case in which deletion‐insertion was detected in the second exon of the N‐ras gene, all ras mutations occurred at codon 12 or 13 of the c‐Ki‐ras gene. All p53 mutations but one were detected in a highly conserved region, and the predominant form of the mutations was G:C→A:T transition at CpG sites in both Japanese and Thai cases, similar to that reported for colorectal cancers. Therefore, in contrast to the ras oncogenes, mutation of the p53 gene was frequently involved in the development of CCCs in both Japanese and Thai patients, irrespective of any difference in etiology.
Transforming growth factor‐β1 expression in Syrian hamster cheek pouch carcinogenesis
Authors: Zenklusen Jean C. , Stockman Sharon L. , Fischer Susan M. , Conti Claudio J. , Gimenez‐Conti Irma B. 
Published: February 2007

AbstractThe expression pattern of transforming growth factor‐β1 (TGF‐β1) during the stages of complete carcinogenesis in the hamster cheek pouch model was studied. The right cheek pouches of 18 male hamsters were treated with 0.5% 7,12‐dimethylbenz[a]anthracene (DMBA) for 16 wk. TGF‐β1 was detected immunohistochemically in the resulting samples with two different polyclonal monospecific antibodies that recognize intracellular and extracellular forms of TGF‐β1. In the normal cheek pouch, extracellular protein stained the corium strongly, but the reaction was not evenly distributed. As treatment progressed, the reaction increased in both area and intensity; the peak was reached at 8 wk. Intracellular TGF‐β1 expression followed a similar pattern, with a peak at 4 wk of treatment. The results of northern blot analysis were concordant with the immunohistochemical results. Overexpression of TGF‐β1 was also observed in the malignant tumors, but only the extracellular form of the protein was present; intracellular TGF‐β1 was not detected in these tumors. The expression of TGF‐β1 in this carcinogenesis model seems to have two formal stages, the first being an overexpression step as a reaction to the uncontrolled growth and the second being one in which tumors have no internal expression of TGF‐β1 but in which external protein accumulates in the surrounding stroma. A possible explanation of this paradox may be that TGF‐β1 has functions other than its growth‐repressing activity. © 1994 Wiley‐Liss, Inc.
Expression of myc, fos, and ha‐ras in the livers of furan‐treated f344 rats and b6c3f1 mice
Authors: Butterworth Byron E. , Sprankle Catherine S. , Goldsworthy Susan M. , Wilson Daniel M. , Goldsworthy Thomas L. 
Published: February 2007

AbstractFuran administered by gavage for 2 yr has been reported to induce hepatocellular carcinomas in male and female B6C3F1 mice and in male but not female F344 rats. Chronic exposure studies in our laboratory using bioassay conditions showed extensive hepatocellular toxicity and sustained increases in regenerative cell proliferation after 1,3, and 6 wk of treatment in male and female rats and male mice. Altered expression of growth‐control genes associated with this hyperproliferative state may enhance the susceptibility of these genes to mutation or may provide a selective growth advantage to preneoplastic cells. Quantitative northern blot analysis of mRNA was used to examine the expression of the oncogenes myc, fos, and Ha‐ras in the livers of animals treated with furan. In male rats, a single administration of 30 mg/kg furan produced necrosis and a subsequent wave of cell proliferation 48 h after treatment and induced transient peaks in the expression of myc, fos, and Ha‐ras 6–24 h after treatment. In male rat liver from our cell proliferation studies, only a slight increase in myc expression was seen at the end of week 1 of treatment. However, beginning at week 3 and increasing at week 6, up to a 15‐fold increase over control values was observed in the expression of myc in the treated animals. The only other notable increase in expression observed in any animals from the cell proliferation study was a threefold increase in myc at week 6 in treated female rats. The absence of an increase in Ha‐ras expression in the male mouse liver suggests that the unique patternof Ha‐ras mutations previously reported in furan‐induced mouse liver tumors is not due to increased mutational susceptibility related to overexpression of this gene. The lack of sustained expression of myc, fos, and Ha‐ras in rapidly proliferating liver suggests that continuous expression of these genes is not necessary to maintain increased rates of cell replication. The large increase in myc expression in male but not female rats suggests an adaptive change that may be related to the sex‐specific incidence of furan‐induced hepatocellular carcinomas in rats. © 1994 Wiley‐Liss, Inc.