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PubMed1991

Early induction of ribonucleotide reductase gene expression by transforming growth factor beta 1 in malignant H-ras transformed cell lines.

Previous investigations have indicated that the suppression of proliferation by transforming growth factor (TGF) beta 1 is often lost upon cellular transformation, and that proliferation of some tumors is stimulated by TGF-beta. The present study provides the first observation of a link between TGF-beta 1 regulation of this process and alterations in the expression of ribonucleotide reductase, a highly controlled rate-limiting step in DNA synthesis. A series of radiation and T24-H-ras-transformed mouse 10T1/2 cell lines exhibiting increasing malignant potential was evaluated for TGF-beta 1 induced alterations in ribonucleotide reductase M1 and M2 gene expression. Early increases in M1 and/or M2 message and protein levels were observed only in malignant cell lines. The TGF-beta 1 induced changes in M1 and/or M2 gene expression occurred prior to any detectable changes in the rates of DNA synthesis, supporting the novel concept that ribonucleotide reductase gene expression can be elevated by TGF-beta 1 without altering the proportion of cells in S phase. T24-H-ras-transformed 10T1/2 cells were transfected with a plasmid containing the coding region of TGF-beta 1 under the control of a zinc-sensitive metallothionein promoter. When these cells were cultured in the presence of zinc, a large induction of TGF-beta 1 message was observed within 1 h. Both M1 and M2 genes were also induced, with increased mRNA levels appearing 2 h after zinc treatment, or 1 h after TGF-beta 1 message levels were clearly elevated. In total, the data suggests a mechanism of autocrine stimulation of malignant cells by TGF-beta 1, in which early alterations in the regulation of ribonucleotide reductase may play an important role.

Animals↗
PubMed1990

[The characteristics of the transformed phenotype and the expression of indicator plasmids in the cells of rat embryonic fibroblasts immortalized by oncogene E1Aad5 and transformed by oncogenes E1Aad5+c-Ha-ras].

Rat embryonal fibroblasts of the second passage have been immortalized or transformed with the E1A region of the human adenovirus type 5 and the cloned c-Ha-ras oncogene. Several cell lines obtained greatly differ according to the criteria of the transformed phenotype: saturation cell density, the ability to be cloned on a substrate and in soft agar, the ability to give tumors in nude mice. We have transiently transfected these immortalized and transformed cell lines with CAT-plasmids containing the CAT gene under the control of promoters of the "cell-cycle dependent" genes (human hsp70 and protooncogene c-fos). The results showed that the expression of hsp-CAT and fos-CAT plasmids differed in great extent depending on whether the cells were immortalized (E1Aad5) or transformed (E1Aad5+Ha-ras). The role of cellular genes and cellular transcription factors influencing the expression of transiently transfected CAT-plasmids has been discussed.

Animals↗
PubMed1989

Detection of transforming growth factor-alpha messenger RNA in normal and chemically transformed hamster oral epithelium by in situ hybridization.

We have recently demonstrated the consistent detection of transforming growth factor alpha (TGF-alpha) in chemically transformed hamster oral tumors. By Northern blot analysis, no TGF-alpha mRNA can be detected in normal cheek pouch mucosa. The consistent expression of TGF-alpha associated with the malignant transformation in the well-defined hamster oral cancer model prompted us to hypothesize that the aberrant expression of this important cellular gene could be related to a specific stage of epithelial alteration. In situ hybridization was used to test this hypothesis. We now report that by in situ hybridization we can detect TGF-alpha mRNA in normal hamster oral epithelium and also at all stages of transformation. In all epithelium, labeling of TGF-alpha mRNA in the basal layer is more pronounced than that observed in the spinous and squamous layers. There is a significant increase of TGF-alpha mRNA labeling early in 7,12-dimethylbenz(a)anathracene-induced oral carcinogenesis. This increase is associated with morphological changes of epithelial hyperplasia or dysplasia. Although lesions exhibiting full-thickness epithelial dysplasia (carcinoma in situ) showed more labeling of TGF-alpha mRNA than do areas of lesser dysplasia, the transition to full-fledged papillary or invasive squamous cell carcinoma is not associated with further elevations of TGF-alpha expression.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1985

Properties of rat cells transformed by DNA plasmids containing adenovirus type 12 E1 DNA or specific fragments of the E1 region: comparison of transforming frequencies.

In this paper, we describe for the first time the transformation of normal rat cells by DNA equivalent to adenovirus type 12 Early Region 1 (E1A). This DNA was 30-fold less efficient at transformation than DNA encoding the entire E1 region. Those established lines expressing a full complement of adenovirus type 12 E1 proteins were phenotypically indistinguishable from adenovirus type 12 virus-transformed cell lines. However, cell lines produced by plasmids carrying subgenomic fragments of E1 DNA and therefore not expressing E1B Mr 52,000 protein took longer to establish and produced tumors only after a protracted latent period. A Giemsa-banding study showed that adenovirus transformation can occur without disruption of the normal rat karyotype.

Adenoviruses, Human↗
PubMed1994

Transforming growth factor beta 1 promotes spontaneous transformation of cultured rat liver epithelial cells.

The neoplastic transformation of cultured rat liver epithelial cells by various means has consistently been associated with the development of resistance to the mito-inhibitory effect of transforming growth factor beta (TGF-beta), suggesting that such phenotype plays a mechanistic role during the transformation of these cells. We have studied the induction of the "TGF-beta-resistant" phenotype in a clonal strain of early passage WB-F344 normal cultured rat liver epithelial cells, the proliferation of which was markedly inhibited by TGF-beta. The control WB cells in continuous culture slowly developed TGF-beta resistance. However, when the same cells were exposed to step-wise increases of TGF-beta concentration in their culture medium, the development of TGF-beta resistance was accelerated. Cells which had been grown in medium containing 1 ng/ml TGF-beta developed colony-forming capacity in soft agar containing epidermal growth factor. Cells which were grown in media containing 5 and 10 ng/ml TGF-beta demonstrated a low level of colony-forming efficiency in soft agar medium without added epidermal growth factor and tumorigenicity in isogeneic rats. These TGF-beta-resistant cells also exhibited progressively increasing levels of expression of the c-fos and and myc mRNA, and increased resistance to the cytotoxicity of Adriamycin and melphalan. The latter phenomenon was accompanied by an increase in the mdr-1 mRNA expression, cellular glutathione level, and glutathione S-transferase activity. The results suggest that chronic exposure to high concentration of TGF-beta promotes the spontaneous neoplastic transformation of cultured rat liver epithelial cells, and that this process may represent one of the mechanisms of cellular adaptation for induction of the multidrug-resistant phenotype during the carcinogenesis of epithelial cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Transforming growth factor-beta1 promotes invasiveness after cellular transformation with activated Ras in intestinal epithelial cells.

Invasion is a defining event in carcinoma progression. In general, invasive carcinoma is characterized by an epithelial-fibroblastoid conversion associated with loss of cell-cell adhesion receptors such as E-cadherin and beta-catenin. We report here that TGF-beta1 promotes the invasiveness by modulating the alterations of cellular plasticity including a loss of cell-cell contact in Ras-transformed epithelial cells. In order to examine the role of TGF-beta1 in the Ras-induced responses, intestinal epithelial cells expressing a conditionally activated Ha-Ras(Val12) (RIE-iRas cells) were used in this study. Induced expression of activated Ha-Ras(Val12) caused morphologic transformation of the RIE-iRas cells with an increase in vimentin expression and a decrease of E-cadherin levels. There was also redistribution of beta-catenin from the cytoplasm to the nucleus after the induction of Ras. TGF-beta1 treatment enhanced both the decrease in E-cadherin levels and the redistribution of beta-catenin. Interestingly, the activation of Ras markedly decreased the level of TGF-beta receptor type II (TbetaRII) in RIE-iRas cells. However, the expression of plasminogen activator inhibitor-1, which is known to be transcriptionally induced by TGF-beta1, was strongly induced by TGF-beta1 despite the marked downregulation of TbetaRII. The induction of Ha-Ras(Val12) markedly increased the invasiveness in RIE-iRas cells, as evaluated by a collagen type I-coated Boyden-chamber assay, and the Ras-mediated invasiveness was significantly enhanced by TGF-beta1 treatment. Expression of a dominant-negative form of TbetaRII in the RIE-iRas cells abrogated both growth-inhibitory and invasion responses to TGF-beta1. Collectively, these results suggest that TGF-beta1 and oncogenic Ras collaborate in promoting cellular invasiveness in intestinal epithelial cells. The enhancement of invasiveness was correlated with decreased E-cadherin levels and subcellular distribution of beta-catenin. The enhancement of oncogenic Ras-mediated cell transformation by TGF-beta1 occurs via TbetaRII.

Adherens Junctions↗
PubMed2002

Transforming growth factor-beta1 modulates matrix metalloproteinase-9 production through the Ras/MAPK signaling pathway in transformed keratinocytes.

Mouse transformed keratinocytes cultured in the presence of transforming growth factor-beta1 (TGF-beta1) acquire a set of morphological and functional properties giving rise to a more motile phenotype that expresses mesenchymal markers. In this work, we present evidence showing that TGF-beta1 stimulates cellular production of MMP-9 (Gelatinase B), a metalloproteinase that plays an important role in tumoral invasion. Our results demonstrate that TGF-beta1stimulates MMP-9 production and MMP-9 promoter activity in a process that depends of the activation of the Ras-ERK1,2 MAP kinase pathway. The latter was demonstrated by cellular transfection of TGF-beta1-sensitive cells with a RasN17 mutant gene, using PD 098059, a MEK 1,2 inhibitor, and treating cells with anti-sense oligodeoxinucleotides. The enhanced MMP-9 production proved to be an important factor in the acquisition of migratory and invasive properties as shown by the use of a specific inhibitor of MMP-9 (GM6001) that inhibits the TGF-beta1-stimulated invasive and migratory properties of these transformed keratinocytes.

Animals↗
PubMed2003

Intestinal transformation results in transforming growth factor-beta-dependent alteration in tumor cell-cell matrix interactions.

BACKGROUND: An alteration in the expression of and response to transforming growth factor-beta 1 (TGF-beta 1) appears to be an important event during colorectal carcinogenesis. However, the precise role of TGF-beta 1 in colorectal carcinogenesis is not clear. We have previously described in detail the changes in cell proliferation and differentiation caused by chronic exposure to TGF-beta 1. In this study we sought to better characterize the changes in tumor cell-cell matrix interactions seen during TGF-beta 1-mediated intestinal transformation. METHODS: Rat intestinal epithelial cells (RIE) and RIE cells transformed by chronic exposure to TGF-beta 1 (RIE-Tr) were treated with TGF-beta 1 and production of components of the plasmin/plasminogen system measured by ELISA and Western blotting. TGF-beta 1 effects on invasion and adhesion were determined in vitro. The role of urokinase on TGF-beta 1-mediated invasion and adhesion were determined using immunoneutralization. The role of COX-2 was determined using a specific COS-2 inhibitor. RESULTS: TGF-beta 1 had no effect on RIE-1 adhesion to collagen types I and IV, fibronectin, and laminin, or invasion through collagen types I and IV. However, 5 ng/mL TGF-beta 1 significantly increased the invasiveness and decreased the adhesiveness of RIE-Tr. This effect of TGF-beta 1 on RIE-Tr was associated with a significant increase in plasmin activity secondary to increased expression of uPA. TGF-beta 1 had no effect on either uPA receptor or PAI-1 in this system. Antibodies to uPA completely blocked the TGF-beta 1-mediated invasiveness of the RIE-Tr cells and returned their adhesiveness to basement membrane proteins to baseline. Addition of the selective Cox-2 inhibitor SC-58125 resulted in a dose-dependent decrease in TGF-beta 1-mediated invasion and uPA expression. CONCLUSION: This study provides additional evidence for TGF-beta 1 as a tumor promoter during intestinal carcinogenesis and a possible new mechanism for Cox-2-related colon carcinogenesis.

Animals↗
PubMed1983

The presence of p53 transformation-related protein in Ab-MuLV transformed cells is required for their development into lethal tumors in mice.

p53, a cellular-encoded protein, is synthesized at elevated levels in a wide range of tumor cells. Ab-MuLV-transformed cells expressing both the viral-encoded p120 oncogene and the cellular-encoded p53 display a lethal tumor phenotype in syngeneic mice. L12 is an exceptional Ab-MuLV-transformed cell line that expresses the p120 oncogene and lacks the p53 cellular protein. Injection of L12 cells into syngeneic mice is followed by the development of local tumors that are subsequently rejected. Prolonged treatment of L12 cells with TPA, a tumor cell promoter, gave rise to L12T cells that synthesize the p53 protein and exhibit a lethal tumor phenotype. Comparison of one-dimensional proteolytic partial peptide map of p53 obtained from L12T to that obtained from other Ab-MuLV-transformed cell lines confirmed their identity. These results suggest a correlation between the cellular expression of p53 in Ab-MuLV-transformed cells and their capacity to develop into lethal tumors in syngeneic mice.

Abelson murine leukemia virus↗
PubMed1989

Continued expression of HPV-16 E7 protein is required for maintenance of the transformed phenotype of cells co-transformed by HPV-16 plus EJ-ras.

The close association between HPV-16 and cervical cancer implies some role for the virus in development of this cancer. Recent studies have shown that the HPV-16 E7 gene encodes the major transforming activity of the virus in baby rat kidney (BRK) cell transformation assays. To investigate the requirement for continued E7 expression in BRK cells transformed by HPV-16 E7 plus EJ-ras, we have developed a system for inducible expression of the E7 gene. The studies reported here show that continued expression of the HPV-16 E7 gene is required for maintenance of the transformed phenotype in these cells. The implications these observations bear on the role of the E7 gene in cervical carcinoma are discussed.

Animals↗
PubMed1981

Reverse transformation of vole cells transformed by avian sarcoma virus containing the src gene.

Vole cells transformed by avian sarcoma virus carrying the src gene lose their fibroblastic morphology, the organized cytoskeletal system of the normal fibroblastic cell, the typical fibronectin deposit around the cell membrane, and the ability to shut off multiplication when suspended in liquid medium. All of these transformation characteristics are reversed by treatment with cAMP derivatives. Moreover, the cAMP treatment does not cause loss of activity of the src gene product. These data imply that cAMP exerts its effect at or after the point in the metabolic pathway affected by the src gene product, pp60src. Presumably, the decision to adopt the transformed or the normal state is determined by the degree to which the src gene or cAMP-mediated kinase activities respectively predominante in the cell. The development of all four transformation characteristics as a result of introduction of the src gene, and their coordinate reversal by cAMP derivatives, supports the previous thesis that in the normal vole or CHO fibroblast all four properties are part of a common regulatory system.

Animals↗
PubMed1983

Induction of reverse transformation and normal cell cycle regulation by dibutyryl cAMP in a chemically transformed cell line.

The objective of this study was to determine whether N6, O2-dibutyryl 3',5'-adenosine monophosphate (db-cAMP)-induced reverse transformation in a chemically transformed mouse cell line, AKR-MCA, would restore normal cell cycle regulation, particularly with regard to their growth arrest in the early G1 period. The AKR-MCA cells were grown to confluency in the presence or absence of db-cAMP (0.5 mM) plus theophylline (1 mM). The confluent cultures were trypsinized and a portion of the cells were fused with mitotic HeLa cells to induce premature chromosome condensation, while the remaining cells were used to study the kinetics of initiation of DNA synthesis. The prematurely condensed chromosomes (PCC) of the control and the treated cultures were classified into G1, S, or G2 types on the basis of their morphology. The G1 PCC were further subclassified into six groups (+1 - +6); +1 being the most condensed and +6 the most decondensed. The cyclic AMP (cAMP)-treated cells exhibited better attachment to the culture dish, were blocked in early G1 period at confluency, and entered S phase about 4 h later than the control following subculturing. In contrast, a majority of cells in the control cultures were arrested in S phase at confluency. These data indicate that the db-cAMP-induced reverse transformation in AKR-MCA cells at least partially restores normal cell cycle regulation in these chemically transformed cells.

Animals↗
PubMed1990

Relationship between chemically induced Ha-ras mutation and transformation of BALB/c 3T3 cells: evidence for chemical-specific activation and cell type-specific recruitment of oncogene in transformation.

BALB/c 3T3 cells were exposed to 7,12-dimethylbenz[a]anthracene (DMBA) and resultant transformed foci were analyzed for the presence of A182----T mutation at codon 61 of Ha-ras (a mutation found in many DMBA-induced animal tumors). None of the 30 independently cloned transformed cell lines contained such a mutation. In order to see whether DMBA is able to induce this mutation in BALB/c 3T3 cells, we developed a method sensitive enough to detect this specific mutation at the frequency of 10(-6). Employing this assay, we found time- and dose-dependent induction by DMBA of Ha-ras A182----T mutation in BALB/c 3T3 cells; for example, 2 wk after exposure to 100 micrograms/mL DMBA, 1.4 in 1 X 10(4) cells contained this specific mutation. On the other hand, other agents that also induce BALB/c 3T3 cell transformation, such as 3-methylcholanthrene (MCA), 12-O-tetradecanoylphorbol-13-acetate (TPA), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), or ultraviolet light, did not induce the mutation at detectable frequency (less than 10(-6)). These results suggest that DMBA efficiently induces Ha-ras mutation in BALB/c 3T3 cells but that this mutation is not recruited in the process of cell transformation. A hypothesis of carcinogen-specific mutation of Ha-ras gene and its tissue (cell type)-specific recruitment in carcinogenesis is proposed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

The products of the E5, E6, or E7 open reading frames of RhPV 1 can individually transform NIH 3T3 cells or in cotransfections with activated ras can transform primary rodent epithelial cells.

Rhesus papillomavirus (RhPV) type 1 was recently shown to cooperate with the activated ras oncogene to transform primary rodent epithelial cells at a level comparable to HPV 16. In similar cotransfection studies, subgenomic portions of RhPV 1 driven by either their natural or a strong heterologous promoter were used in primary baby rat kidney cells to demonstrate that transforming properties of RhPV 1 could be localized individually to the E5, E6, and E7 open reading frames. Fully transformed cells were observed when either E5 or E7 were downstream of a strong heterologous promoter. Similarly, either E6 or E6 and E7 downstream of the native promoter fully transformed these cells as determined by immortalization, anchorage independent growth and tumorigenicity studies.

3T3 Cells↗
PubMed1981

Plasmid transformation in Bacillus subtilis. Alterations introduced into the recipient-homologous DNA of hybrid plasmids can be corrected in transformation.

Various alterations (deletions, additions, inversions) were introduced into portions of pC194/B. subtilis or pC194/phi 105 hybrid plasmid molecules which are homologous to the DNA of recipients in transformation. These plasmids are stably maintained in transformations of recombination deficient cells. In transformations of recombination proficient cells, they can be corrected to those plasmid forms into which the alterations were originally introduced. This correction is most pronounced when transformations are performed with monomeric ccc forms of hybrid plasmids. It is suggested that correction is a consequence of mismatch repair occurring in the synapsis of homologous portions of plasmid and resident DNAs.

Bacillus subtilis↗
PubMed1996

Construction of Hermes shuttle vectors: a versatile system useful for genetic complementation of transformable and non-transformable Neisseria mutants.

A versatile shuttle system has been developed for genetic complementation with cloned genes of transformable and non-transformable Neisseria mutants. By random insertion of a selectable marker into the conjugative Neisseria plasmid ptetM25.2, a site within this plasmid was identified that is compatible with plasmid replication and with conjugative transfer of plasmid. Regions flanking the permissive insertion site of ptetM25.2 were cloned in Escherichia coli and served as a basis for the construction of the Hermes vectors. Hermes vectors are composed of an E. coli replicon that does not support autonomous replication in Neisseria, e.g. ColE1, p15A, or ori(fd), fused with a shuttle consisting of a selectable marker and a multiple cloning site flanked by the integration region of ptetM25.2. Complementation of a non-transformable Neisseria strain involves a three-step process: (i) insertion of the desired gene into a +Hermes vector; (ii) transformation of Hermes into a Neisseria strain containing ptetM25.2 to create a hybrid ptetM25.2 via gene replacement by the Hermes shuttle cassette; and (iii) conjugative transfer of the hybrid ptetM25.2 into the final Neisseria recipient. Several applications for the genetic manipulation of pathogenic Neisseriae are described.

Base Sequence↗
PubMed1987

Collagen-fibronectin interactions in normal and Rous sarcoma virus-transformed avian tendon cells: possible mechanisms for increased extracellular matrix turnover after transformation.

Using gelatin, casein, and fibronectin as substrates and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), we have identified protein-degrading enzymes in both normal and Rous sarcoma virus-transformed primary avian tendon cells. Although there are some consistent differences in the profile of the gelatinolytic activities (mainly metalloproteinases) between normal and transformed cells, the amounts of fibronectin-degrading activities seem to be comparable. In vitro studies reported here demonstrate that the degradation of fibronectin is partially and specifically inhibited by gelatin and collagen. We therefore propose that the abundant collagen present in normal tendon cells protects fibronectin against degradation. Conversely, in transformed cells, where collagen levels are drastically reduced, fibronectin may be more accessible to degradation. Thus differences in the steady-state levels of fibronectin on normal and transformed cells may be, at least in part, a consequence of changes in collagen levels.

Animals↗
PubMed2005

Genetic transformation of Tylophora indica with Agrobacterium rhizogenes A4: growth and tylophorine productivity in different transformed root clones.

We have developed an efficient transformation system for Tylophora indica, an important medicinal plant in India, using Agrobacterium rhizogenes strains LBA9402 and A4 to infect excised leaf and stem explants and intact shoots at different sites. The induction of callus and transformed roots was dependent on the bacterial strain, explant type and inoculation site used. Transformed roots were induced only in explants infected with A. rhizogenes strain A4, while an optimal transformation frequency of up to 60% was obtained with intact shoots inoculated at the nodes. The presence of the left-hand transferred DNA (T(L)-DNA) in the genome of T. indica roots induced by A. rhizogenes was confirmed by PCR amplification of the rooting locus genes of A. rhizogenes. Root growth and the production of tylophorine, the major alkaloid of the plant, varied substantially among the nine root clones studied. Both parameters increased over time in liquid cultures, with maximum biomass and tylophorine accumulation occurring within 4-6 weeks of growth in fresh medium. Interestingly, in liquid culture, the culture medium also accumulated tylophorine up to concentrations of 9.78+/-0.21 mg l(-1).

Alkaloids↗