bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for a p53‐independent pathway for upregulation of SDI1/CIP1/WAF1/P21 RNA in human cells
Authors: Johnson Mac , Dimitrov Diana , Vojta Patrick J. , Barrett J. Carl , Noda Asao , Pereira‐Smith Olivia M. , Smith James R. 
Published: February 2007

AbstractSDI1 is an inhibitor of DNA synthesis that we isolated by expression screening cDNAs prepared from senescent, terminally nondividing human cells. Other groups then cloned this gene as a cyclin‐dependent kinase (cdk)‐interacting protein (CIP1, p21) that inhibits cdks; the gene was also isolated by screening for genes transactivated by p53 (WAF1). p53 levels are low in senescent and quiescent contact‐inhibited or serum‐deprived normal human cells, which we have found express high levels of SDI1 mRNA. This indicates that alternate pathways for upregulation of message level of this gene may exist. We therefore proceeded with the study presented here, treating human cells with a variety of growth‐arrest‐inducing agents, including some that damaged DNA, and found that RNA levels of SDI1 were increased in all cases that resulted in growth inhibition. More important, with the exception of γ‐radiation, most of these agents were able to elevate SDI1 message levels in cells lacking wild‐type p53. At least two distinct kinetic profiles for RNA induction were observed, one that implicated p53 transactivation and occurred early enough to cause arrest, and another that clearly was p53 independent and suggested a role for the SDI1 gene product in the maintenance rather than in the cause of inhibition of DNA synthesis. ©1994 Wiley‐Liss, Inc.
Articles activation of promutagens in a human bronchial epithelial cell line stably expressing human cytochrome P450 1A2
Authors: Macé Katherine , Gonzalez Frank J. , McConnell Ian R. , Garner R. Colin , Avanti Ornella , Harris Curtis C. , Pfeifer Andrea M. A. 
Published: February 2007

AbstractNormal human bronchial epithelial (NHBE) cells are the putative progenitor cells of all types of lung cancer. NHBE cells immortalized by SV40 T‐antigen retain many characteristics of the primary cells and are a useful model for investigating the role of oncogenes, tumor suppressor genes, and certain chemical carcinogens in the molecular pathogenesis of lung cancer. In this study, SV40 T‐antigen‐positive cells (BEAS‐2B) were characterized for their metabolic functions and were shown to continue to express epoxide hydrolase, glutathione S‐transferrase π, glutathione peroxidase, and catalase. To increase their metabolic activity towards human procarcinogens, human cytochrome P450 1A2 (CYP1A2) was stably expressed by introducing CYP1A2 cDNA into BEAS‐2B cells either by infection with a high‐titer recombinant retrovirus (pXT‐1A2) or by transfection with a CYP1A2 expression vector (pCMV1A2), which produced the cell lines B‐1A2 and B‐CMV1A2, and B‐CMV1A2, respectively. Cell lines established with either expression system expressed enzymatically active CYP1A2 protein and were 50‐ to 400‐fold more sensitive to the cytotoxic effect of the carcinogen aflatoxin B1) (AFB1) than the corresponding control cell lines. The cytotoxic effects of AFB1 were paralleled by increased metabolism of AFB1 and enhanced formation of the AFB1‐N7 guanine adduct in B‐CMV1A2 cells. Cytotoxicity and adduct formation correlated with a significantly higher protein expression of CYP1A2 by the cytomegalovirus promoter‐driven plasmid. Since this human epithelial cell line is the precursor cell type of lung cancer, has normal phase II enzymes, and exhibits highly reproducible expression of phase l enzymes, this in vitro model should aid in the evaluation of putative human carcinogens and anticarcinogens. ©1994 Wiley‐Liss, Inc.
Preferential primary‐response gene expression in promotion‐resistant versus promotion‐sensitive JB6 cells
Authors: Cmarik Joan L. , Herschman Harvey , Colburn Nancy H. 
Published: February 2007

AbstractThe 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA)‐inducible sequence (TIS) genes are a set of primary response genes induced in Swiss 3T3 cells by TPA. They include three transcription factors, a prostaglandin synthase, and three proteins of unknown function. To ascertain which, if any TIS genes might be involved in tumor promotion, we examined the expression of these genes in response to tumor promoters in transformation promotion‐sensitive (P+) and ‐resistant (P‐) JB6 murine epidermal cells, a model used to identify events relevant to promotion. A subset of TIS genes (TIS1,TIS21), TIS10, and TIS21) was preferentially induced by TPA in P‐cells. In addition, TIS1 and TIS21 mRNAs were preferentially induced in P‐cells by epidermal growth factor, another transformation promoter that distinguishes P+ from P‐ cells. TIS1 and TIS21 protein levels were also greater in TPA‐treated P‐ cells than P+ cells. Forskolin, a cAMP‐elevating anti‐promoter, increased TPA‐induced levels of TIS1, TIS10, and TIS21 mRNAs in P+ cells, ruling in potential roles for these genes in modulating tumor promotion. The anti‐promoters fluocinolone acetonide, retinoic acid, and superoxide dismutase did not enhance TPA‐induced levels of TIS1 and TIS21 mRNAs in P+ cells, suggesting that these inhibitors may act on other promotion‐relevant genes. TIS1 encodes a member of the steroid receptor superfamily. TIS21 encodes a protein of unknown function with strong sequence similarity to BTG1, a proposed “anti‐proliferative gene” (Rouault JP, Rimokh R, Tessa C, et al., EMBO J 11:1663–1670, 1992). Preferential induction by multiple promoters of these TIS genes in P‐ cells and enhancement of their induction in P+ cells by the anti‐promoter forskolin make TIS1 and TIS21 candidates for promotion suppressor genes. ©1994 Wiley‐Liss, Inc.
Polyamine‐dependent expression of the matrix metalloproteinase matrilysin in a human colon cancer—derived cell line
Authors: Wallon U. Margaretha , Shassetz L. Richard , Cress Anne E. , Bowden G. Tim , Gerner Eugene W. 
Published: February 2007

AbstractMatrilysin, which is a member of the matrix metalloproteinase family and is implicated in colon cancer invasion, is expressed in human colon adenocarcinoma—derived SW1116 cells. We investigated the effect of α‐difluoromethylornithine (DFMO) on matrilysin expression in this cell line because others have shown that DFMO can inhibit invasion and carcinogenesis in epithelial tissues, including the colon, in experimental models. DFMO reduced extracellular levels of matrilysin protein after 4 d of treatment. Intracellular levels of matrilysin protein were minimally affected by DFMO treatment. The decrease in extracellular matrilysin protein levels caused by DFMO was not a consequence of lowered steady‐state levels of matrilysin mRNA. After 4 d of exposure, the amount of this transcript was higher in DFMO‐treated cells than in untreated cultures, whereas the mRNA stabilities were similar. These data show that polyamine depletion by DFMO can suppress the expression of matrilysin, a gene product thought to be involved in tumor invasion. The decrease in extracellular matrilysin protein caused by DFMO treatment appears to be due to a posttranscriptional mechanism, although transcription of this gene also seems to be affected by polyamines in SW1116 cells. ©1994 Wiley‐Liss, Inc.
Induction of activating mutations in the human c‐Ha‐ras‐1 proto‐oncogene by oxygen free radicals
Authors: Du Ming‐Qing , Carmichael Paul L. , Phillips David H. 
Published: February 2007

AbstractThe mutagenicity of oxygen free radicals was studied in a forward mutation system. pEC plasmid containing the human c‐Ha‐ras‐1 proto‐oncogene was reacted with oxygen free radicals generated by Cu2+ and H2O2 and was then transfected into NIH/3T3 cells. Transformed foci were observed with oxygen free radical—modified DNA but not with unmodified DNA. The mutations responsible for the Ha‐ras‐1 gene activation in 11 transformed foci were characterized. G→T mutations at the second base of codon 12 were found in two transformed foci, A→T transversions at the second base of codon 61 in five foci, and G→T mutations at the third position of codon 61 in four transformed foci. These observed mutations are identical to those commonly found in human skin carcinomas, suggesting that reactive oxygen species may play an important role in the carcinogenesis of these tumors. Interestingly, a significant proportion of mutations was found at the second and third base of codon 61 (CAG). In a previous study, the same oxygen free radical—generating system was found to cause an intrastrand cross‐link between adjacent purine nucleotides at AG sites in DNA (Carmichael et al., Carcinogenesis 13:1127–1135, 1992). These data demonstrate that oxygen radicals can induce DNA damage that can result in a specific activation of a human proto‐oncogene. ©1994 Wiley‐Liss, Inc.
Differential expression of prostaglandin h synthase isozymes during multistage carcinogenesis in mouse epidermis
Authors: Müller‐Decker Karin , Scholz Kirsten , Marks Friedrich , Fürstenberger Gerhard 
Published: February 2007

AbstractAn anti–tumor‐promoting effect of indomethacin and related nonsteroidal anti‐inflammatory drugs (NSAIDs) as well as the ability of the tumor promoter 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) to increase the level of prostaglandins in murine keratinocytes and mouse epidermis in vivo has been repeatedly documented. Here, the expression of prostaglandin H synthase (PGHS) isozymes, which are major targets of NSAIDs, was investigated in different stages of tumor development in mouse skin. Mouse epidermis in vivo constitutively expressed PGHS‐1. PGHS‐1 steady‐state levels remained unchanged upon induction of acute or chronic epidermal hyperplasia by TPA and in papillomas and carcinomas generated by the initiation‐promotion procedure, with 7,12‐dimethylbenz[a]anthracene as initiator and TPA as promoter. Thus, the elevated prostaglandin level in the acute hyperplastic epidermis was very likely due to PGHS‐2 induction. Repeated applications of TPA resulted in stationary hyperplasia and downregulation of PGHS‐2 expression and prostaglandin levels, suggesting that the epidermis had adapted to the TPA stimulus. In papillomas and carcinomas, however, constitutive overexpression of PGHS‐2 was found, with a large amount of prostaglandin E2 and prostaglandin F2α. Keratinocyte cell lines corresponding to different stages of tumor development also constitutively over‐expressed PGHS‐2. Considered with inhibitor studies, these data suggest that PGHS‐2 has a critical role in skin carcinogenesis. The anti–tumor‐promoting effect of the PGHS inhibitor indomethacin is specifically reversed by prostaglandin F2α, indicating that this prostaglandin type has a significant role in tumor development. © 1995 Wiley‐Liss Inc.
Hyperpigmentation and melanocytic hyperplasia in transgenic mice expressing the human T24 HA‐ras gene regulated by a mouse tyrosinase promoter
Authors: Powell Marianne Broome , Hyman Paul , Bell O. Dianna , Balmain Allan , Brown Ken , Alberts Dave , Bowden G. Tim 
Published: February 2007

AbstractThe tyrosinase promoter has been used to target expression of the mutated human T24 Ha‐ras oncogene in pigment‐producing cells of transgenic mice. Two independent founder mice carrying the transgene survived and showed the same distinct phenotype of muted coat color, deeply pigmented skin with multiple nevi, and twirling behavior. The offspring of one of these founders were developed into a line that stably expressed the same phenotype. Histopathological analysis of the tissues revealed hyperpigmentation and/or melanocytic hyperplasia in the skin, eyes, inner ear, and meningeal membranes in the brain. Reverse transcriptase‐polymerase chain reaction analysis revealed expression of the transgene in skin, brain, and spleen. We propose that these transgenic mice will be a model for studying the process of multistage melanoma carcinogenesis and a system for evaluating potential chemopreventive agents. © 1995 Wiley‐Liss Inc.
The p53 and mdm‐2 genes in human testicular germ‐cell tumors
Authors: Riou Guy , Barrois Michel , Prost Sandrine , Terrier Marie Josée , Theodore Christine , Levine Arnold J. 
Published: February 2007

AbstractMutations in the p53 gene are common in many cancers. They have been documented to occur in about 55% of all cancers of 51 different cell and tissue types. These mutations are accompanied by overexpression of the p53 protein in the nucleus of the cell, and this protein has lost its tumor suppressor function. In this study, 25 testicular germ‐cell (TGC) tumors were tested for p53 mutations and the level of p53 protein expression. While 67% of the tumors overproduced the p53 protein in the nucleus of 10‐60% of their cells, in all cases the DNA sequence of exons 4‐9 of the p53 gene was wild type. In this tumor type, there was apparently no selection pressure for p53 mutations. The mdm‐2 gene resides on chromosome 12 (12q13‐q14), a chromosome often altered in TGC tumors. mdm‐2 gene amplification (2.5‐ to 10‐fold) was detected in three (12%) of these TGC tumors. These three tumors, and eight additional TGC tumors, overexpressed mdm‐2 mRNA. There was a good correlation between overexpression of p53 protein and overexpression of mdm‐2 mRNA (P = 0.01). This may well result from the fact that the level of mdm‐2 mRNA is regulated by the p53 level. These studies demonstrate that TGC tumors fail to be selected for p53 mutations but nonetheless frequently expressed high levels of wild‐type p53 protein in the cell nucleus. Perhpas this produces the excellent response to radiation and chemotherapy of these tumors, which generally have a good prognosis. Wild‐type p53 may mediate apoptosis in these cells in response to the DNA damage. © 1995 Wiley‐Liss Inc.
Regulatory elements in the first intron of the mouse ha‐ras gene
Authors: Telliez Jean‐Baptiste , Plumb Mark , Balmain Allan , Bailleul Bernard 
Published: February 2007

AbstractThe Ha‐ras gene is one of the three oncogenes (Ha‐ras, Ki‐ras, and N‐ras) of the ras superfamily of small G proteins. The p21ras proteins encoded by the ras genes are key proteins involved in the transduction of signals from membrane receptor‐tyrosine kinases to downstream targets. The ras genes seem to play a ubiquitous role in the control of cell proliferation and cell differentiation. At the same time, ras genes may perform specific differentiated functions in certain cell types. Little is known about the regulation of expression of the Ha‐ras gene. The first intron of the Ha‐ras gene has been reported to be highly conserved between human and rodent. We investigated the role that this intron may play in the regulation of expression of Ha‐ras. The promoter region of the Ha‐ras gene exhibits characteristics of a housekeeping gene. Deletion analysis shows the existence of an enhancer‐type element in the 5′ region of the first intron (intron 0). DNase I footprinting experiments reveal five sites that interact with nuclear proteins from fibroblast and epithelial cell lines. Deletion and site‐directed mutagenesis of three of these sites show that two are involved in a positive effect and one in a negative effect on the regulation of expression of the mouse Ha‐ras gene. © 1995 Wiley‐Liss Inc.
c‐jun and multistage carcinogenesis: Association of overexpression of introduced c‐jun with progression toward a neoplastic endpoint in mouse JB6 cells sensitive to tumor promoter‐induced transformation
Authors: Watts Rebecca G. , Ben‐Ari Elia T. , Bernstein Lori R. , Birrer Michael J. , Winterstein Dolores , Wendel Edmund , Colburn Nancy H. 
Published: February 2007

AbstractTumor promoters such as 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) and epidermal growth factor (EGF) induce neoplastic transformation, elevated c‐jun protein expression, and activator protein‐1 (AP‐1)‐dependent gene expression in JB6 mouse epidermal cells sensitive to tumor promoters (clone 415a P+ cells). In contrast, JB6 cells resistant to tumor promoter‐induced transformation (clone 307b P‐ cells) exhibit a greatly reduced TPA or EGF inducible c‐jun expression and AP‐1 activity. We have recently shown that induced AP‐1 is necessary for tumor promoter‐induced transformation of P+ cells because introduction of a dominant negative c‐jun mutant into P+ cells inhibits both AP‐1 dependent transactivation and the transformation response to tumor promoter. The intent of the investigation presented here was to test the hypothesis that elevation of AP‐1 activity is sufficient to cause progression to the P+ phenotype in P‐cells or to the transformed phenotype in P+ cells. Clonally derived P+ and P‐ recipient cells transfected with a human c‐jun expression construct and overexpressing c‐jun protein were tested for progression by assaying for constitutive or inducible anchorage independent phenotype and nude‐mouse tumorigenicity. Overexpression of c‐jun did not produce progression in P‐ cells but did increase the probability of progression in P+ cells (two of five transfectant cell lines progressed to the tumor phenotype). In addition, c‐jun overexpression did not increase AP‐1 activity in any of the P‐/c‐jun transfectants or in the two of five P+/c‐jun transfectants that acquired the transformed phenotype. The P+/c‐jun transfectants that showed elevated AP‐1 activity did not progress to the tumor phenotype, demonstrating that an increase in AP‐1 activity is insufficient for this progression. Since P+‐to‐tumor phenotype progression occurred in cells overexpressing c‐jun but not AP‐1, we propose that P+‐to‐transformed phenotype progression is c‐jun dependent and AP‐1 independent. © 1995 Wiley‐Liss, Inc.
Transcriptional repression of smooth‐muscle α‐actin gene associated with human papillomavirus type 16 E7 expression
Authors: Nishida Makoto , Miyamoto Shingo , Kato Hidenori , Miwa Takeshi , Imamura Toshiro , Miwa Katsuhiro , Yasumoto Shigeru , Barrett J. Carl , Wake Norio 
Published: February 2007

AbstractTo explore the role of the E7 viral oncogene from human papillomavirus type 16 (HPV16) in the regulation of cytoskeletal organization, we investigated alterations in particular cytoskeletal components in rat embryonal fibroblasts and three transformants of rat embryonal fibroblast cells produced by transfertions with HPV16 E7 alone (TF1), HPV16 E7 plus adenovirus type 5 E1B (TF3), and HPV16 E7 plus activated Ha‐ras (TF4). Marked reductions in smooth‐muscle (SM) a‐actin content and disrupted organization of stress fibers detected by anti—SM α‐actin antibody were evident in all the transformants. These cytoskeletal manifestations were associated with a significant reduction in the mRNAs in these cells. Transcriptional repression by the E7 gene was observed after transient transfection of a chloramphenicol acetyltransferase reporter gene with SM α‐actin gene promoter. Nucleotides —123 to —39 of the SM α‐actin gene promoter were required for the HPV16 E7 transcriptional repression as shown by the chloramphenicol acetyltransferase assay. The downregulation of this actin isoform mediated by the E7 oncoprotein may play an important role in cell transformation by HPV16. © 1995 Wiley‐Liss, Inc.
p53 mutations in matched primary and metastatic human tumors
Authors: Peller Shoshana , Halevy Ariel , Slutzki Sam , Kopilova Yulia , Rotter Varda 
Published: February 2007

AbstractMutations in thep53 tumor suppressor gene have been found to be the most frequent genetic alterations in human malignancies. To further examine the idea that neoplastic progression is associated with mutations in the p53 gene, we analyzed matched primary and metastatic tumor samples. The samples included 15 pairs of breast cancer and metastases to lymph nodes, four pairs of gastrointestinal adenocarcinomas and metastases to liver, one colon adenocarcinoma and metastasis to a lymph node, and one lung carcinoma and metastasis in the pleura. Genomic DNA or cDNA from each tumor sample was amplified by the polymerase chain reaction and labeled by using one biotinylated primer. The DNA strands were separated with magnetic streptavidin beads and sequenced directly. p53 mutations were detected in 11 of 21 patients (52%) in either primary tumors, metastases, or both. In six of these patients the primary tumor and matched metastasis shared the same single mutation. In the other patients an additional mutation in the primary tumor only or a mutation in the metastasis only was observed. Our data suggest that tumor development and progression toward metastasis involves structural alterations in the ps3 gene that occur early in carcinogenesis. In some cases, genetic changes in metastatic spreading may also include the appearance of a mutation in a metastasis derived from a primary tumor expressing wild‐type p53, a selection of metastatic cells with a single mutation from a primary tumor expressing two different mutations, or loss of heterozygosity. © 1995 Wiley‐Liss, Inc.
How are potent bulky carcinogens able to induce such a diverse array of mutations?
Authors: Loechler Edward L. 
Published: February 2007

AbstractMutations induced by activated benzo[a]pyrene ((+)‐anti‐B[a]PDE) in Escherichia coli are being investigated, by using both random and adduct‐site–specific mutagenesis approaches. A working hypothesis was proposed that the major adduct of (+)‐anti‐B[a]PDE (formed at N2‐Gua) is able to induce different base‐substitution mutations (e.g., GC→TA vs. GC→AT) depending upon its conformation in DNA, which can be influenced by various factors, notably DNA sequence context. Frameshift mutations are also common with (+)‐anti‐B[a]PDE, and other work suggested that the frameshift and base‐substitution mutagenesis pathways are coupled. The simplest hypothesis to rationalize this interrelationship is that a single (+)‐anti‐BEa[a]PDE adduct in a single conformation can be bypassed via either a frameshift or a base‐substitution pathway. This counterintuitive notion can be reconciled if there are two different kinds of conformations on the pathway to mutagenesis: a class I conformation, which is the initial conformation of a DNA adduct in double‐stranded DNA before its encounter with a DNA polymerase, and a class II conformation, which is the conformation that forms at a single‐strand/double‐strand DNA junction during replication by a DNA polymerase. Thus, GC→TA and GC→AT mutations may be induced by different class I conformations, whereas base substitution and frameshift mutations may be induced by the same class I conformation but by different class II conformations. The pathway of mutagenesis would be dictated by the relevant class I and II conformations, which in turn would be controlled by various factors, notably DNA sequence context. © 1995 Wiley‐Liss, Inc.