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PubMed1990

Increased tyrosine phosphorylation in ras transformed fibroblasts occurs prior to manifestation of the transformed phenotype.

Murine fibroblasts transformed by ras oncogenes exhibited an increased amount of tyrosine phosphorylated proteins compared to normal cells. The pattern of phosphorylation was similar to that observed in cells chronically stimulated with EGF or PDGF, and is probably due to autocrine stimulation of receptor tyrosine kinases. NIH 3T3 cells transfected with H-ras under the control of a glucocorticoid inducible promoter were used to determine the temporal relationship among expression of p21H-ras oncoprotein, increase in tyrosine phosphorylation and appearance of the transformed morphology. Enhanced tyrosine phosphorylation was observed more than 24 hours before evidence of morphological changes. These results suggest that full transformation by ras oncogenes requires cooperation with tyrosine protein kinases.

Actins↗
PubMed1978

Factors affecting the binding of polycyclic aromatic hydrocarbons to human embryo cells, and transformable and non-transformable hamster embryo cells.

The effects of various factors, including population doubling number, percent of confluence, serum concentration and storage in liquid nitrogen on the binding of several polycyclic aromatic hydrocarbons to human and hamster embryo cells were studied. The binding of 7,12-dimethylbenz[a]-anthracene (DMBA) to hamster embryo cells DNA, RNA and protein was maximal after 22 h of treatment. In contrast, binding to human embryo cell macromolecules increased for at least 55 h. Treatment of hamster embryo cells at 100% confluence resulted in much less binding than treatment at 70% confluence, whereas with human embryo cells the binding increased, or remained constant, following treatment at the greater confluence. The transforming frequency of hamster embryo cells decreases with increasing population doubling number. Accordingly, we found that the binding of DMBA to hamster embryo DNA, RNA and protein decreased approximately 100-fold between population doubling numbers 8 and 20. In transformable cell cultures, DMBA was bound to hamster embryo cell DNA to a greater extent than to RNA or protein. The binding of DMBA to nucleic acids was much greater than binding by either dibenz[a,h]anthracene (DB[a,h]A) or dibenz-[a,c]anthracene (DB[a,c]A), both of which had low binding values at all population doubling numbers tested. Therefore, the best correlation of binding with carcinogenicity and transforming activity was observed with DMBA. Storage of hamster embryo cells in liquid nitrogen did not alter their binding characteristics. Binding of all three hydrocarbons to human embryo cell nucleic acids was low during all population doubling numbers studied, while binding to cellular protein increased until population doubling number 70 and then decreased sharply.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1984

Regulation of lysosomal autophagy in transformed and non-transformed mouse fibroblasts under several growth conditions.

The role of the lysosomal system in accelerated protein degradation was investigated in 3T3 mouse fibroblasts and in the SV40 virus-transformed derivative, SV3T3. Rates of protein degradation and quantitative electron microscopic alterations in the lysosomal system were compared under four different growing conditions: exponential growth, confluent phase, serum deprivation, and confluent phase together with serum deprivation. We found a significant correlation between increases in rates of proteolysis of long-lived proteins and fractional volume of lysosomes, suggesting a causal relationship between the two, as well as a morphological explanation for the differences in rates of protein degradation in transformed and non-transformed cultured cells. The increase in lysosomal fractional volume resulted from an increase in dense bodies only (in serum-deprived exponential or confluent cultures) or from an increase in autophagic vacuoles and dense bodies (in serum-supplemented confluent cultures).

Animals↗
PubMed1985

Inhibition of carcinogen-induced cellular transformation of human fibroblasts by drugs that interact with the poly(ADP-ribose) polymerase system. Initial evidence for the development of transformation resistance.

Two types of interactions of 13 drugs with human fibroblasts were determined: I50 of nuclear poly(ADP-ribose) polymerase, as assayed with isolated nuclei in vitro, and the non-toxic concentration of drugs that prevented carcinogen-induced cell transformation of intact fibroblasts (RCF1). In general, RCF1 was much lower than I50, and one antitransformer did not inhibit the enzyme in vitro, indicating that low-affinity enzyme inhibitory sites appear to play no role in the mechanism of prevention of cell transformation. Two enzyme inhibitors, caffeine and 1-methylnicotinamide, exhibited no antitransforming activity. Benzamide when applied in population doubling 1 induced resistance to cell transformation in population doubling 6 by carcinogens added at this stage.

Acetamides↗
PubMed1992

Small deletion in v-src SH3 domain of a transformation defective mutant of Rous sarcoma virus restores wild type transforming properties.

RSV mutant virus PA101T was obtained while assaying the tumorigenicity of parental PA101 virus in chickens. PA101 is a transformation defective mutant of RSV which has a low src kinase activity. However, PA101 retained a temperature-sensitive ability to induce sustained proliferation of neuroretina cells. PA101T appeared as a wild-type phenotype revertant of PA101. Molecular cloning and sequencing of PA101T showed that this reversion is due to additional mutations in PA101 src gene. These mutations are a deletion eliminating three amino acids in the N-terminal region of SH3 domain and mutation of Ala 426 to Val. Analysis of the properties of chimeric src genes associating either half of PA101T with the complementary regions of PA101 or wild-type virus showed that the N-terminal moiety of PA101T src, which contains the deletion, confers wild-type transforming properties, whereas its C-terminal moiety, which contains single amino acid mutation, confers a partially temperature-sensitive phenotype. These results are consistent with other reports showing that mutations or deletions in this region of SH3 activate the transforming potential of c-src. They support the hypothesis that the N-terminal region of SH3 interacts with a cellular negative regulator of src activity.

Amino Acid Sequence↗
PubMed1976

Insulin receptors in normal and transformed fibroblasts: relationship to growth and transformation.

The insulin receptors in normal and transformed lines of mouse Balb/3t3 fibroblasts have been studied. In the normal fibroblasts, the binding of insulin was low in growing cells and increased 2-9 fold in confluent stationary cells. Insulin binding was increased whether growth arrest was due to contact inhibition of growth or serum starvation. When serum-starved cells were stimulated to grow by the addition of fresh serum, insulin binding declined. In cells transformed by simian virus 40, Kirsten, Moloney, and Harvey sarcoma viruses, methylcholanthrene, X rays, or spontaneously, the binding was low, in the same range as growing normal cells. In simian virus 40-transformed cells, insulin binding increased 4 fold as the cells reached higher densities in culture. No relationship to changes in cell size was found. The differences in binding were due to changes in the concentration of the receptors, without changes in their affinity for the hormone.

Blood↗
PubMed1984

Transformation of several species of higher plants by Agrobacterium rhizogenes: sexual transmission of the transformed genotype and phenotype.

The T-DNA of the Ri plasmid from Agrobacterium rhizogenes is compatible with the regeneration of whole plants from genetically transformed roots and is transmitted through meiosis to the progeny of genetically transformed plants in carrot, tobacco, and morning glory (Convolvulus arvensis). The presence of Ri T-DNA is correlated with a phenotype that in some respects is invariable from species to species and in other respects varies as a function of species, organ clone within species, or individual. The transformed phenotype concerns a variety of morphological and physiological traits, is dominantly inherited in tobacco, but does not in general appear to be deleterious. The Ri T-DNA may provide a molecular starting point for studying a number of basic phenomena in plant morphology and physiology.

Genotype↗
PubMed1984

Transformation-associated changes in nuclear-coded mitochondrial proteins in 3T3 cells and SV40-transformed 3T3 cells.

Comparative two-dimensional gel electrophoretic studies were performed on mitochondrial proteins in nontransformed mouse 3T3 cells and in SV40-transformed 3T3 cells, SV-T2. Two polypeptides, of 58 and 40 kDa, were present in increased amounts in SV40-transformed cells. These polypeptides were demonstrated to be nuclear-coded mitochondrial proteins by their absence in mitochondrial preparations, when labeling was performed in the presence of a mitochondrial-specific inhibitor, Rhodamine 6G. Temperature-sensitive mutants for transformation were derived from 3T3 cells by transfection with cloned SV40 DNA containing the ts A58 mutation. Increased amounts of the 58 kDa protein were apparent in these cells at the permissive temperature (33 degrees C) compared to the restrictive temperature (39.5 degrees C).

Animals↗
PubMed1990

Transformed fat storing cells inhibit the proliferation of cultured hepatocytes by secretion of transforming growth factor beta.

Conditioned medium from secondary cultures of fat storing cells (transformed fat storing cells) inhibits replicative (hydroxyurea-sensitive) DNA synthesis dose-dependently in primary cultures of hepatocytes stimulated in vitro by transforming growth factor (TGF) alpha. Similarly, [3H]thymidine incorporation into the DNA of hepatocytes from the regenerating rat liver is reduced by about 70% by fat storing, cell conditioned medium. Medium which had been transiently acidified was more potent than native medium. It displaced [125I]TGF-beta from binding sites on the hepatocyte surface and the inhibitory activity was completely blocked by anti-TGF-beta antibodies. From binding studies, a TGF-beta concentration of 1.8 +/- 0.4 ng/ml conditioned medium produced by 2 X 10(5) cells per 24 h was estimated. Transformed, but not primary, cultures of fat storing cells at an early state produce and secrete TGF-beta, which reduces hepatocellular proliferation significantly.

Animals↗
PubMed1986

Co-cultured transformed and untransformed C3H 10T1/2 cells: preferential killing of transformed cells by low dose rate irradiation.

Co-cultured C3H 10T1/2 cells, in which transformed cells were grown as discrete colonies on top of density-inhibited monolayers of untransformed cells, were used to determine the potential usefulness of a short term assay system for the study of differential radiation effects as they may apply to cell populations with differing turnover rates, but in close physical contact. Mixed cultures were exposed to either an acute dose of 20 Gy of Cs-137 gamma rays, or a dose of 72 Gy delivered at a low dose rate of 0.34 Gy per hour. These treatments resulted in approximately equal levels of damage to the untransformed monolayers. At 10-day intervals after treatment, representative flasks from each dose group were examined for evidence of degeneration, and subsequent regrowth, if any, of the transformed colonies and untransformed monolayers. For comparable amounts of visible damage to the untransformed monolayers, the low dose rate irradiation was more effective at delaying regrowth of, or even eradicating, transformed colonies. These results are consistent with expectations based on previous results in which dose-rate or dose fractionation isoeffect curves were compared for these two cell types, grown independently in plateau phase cultures.

Animals↗
PubMed2004

Transforming growth factor beta (TGFbeta) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT).

Formation of the medial edge epithelial (MEE) seam by fusing the palatal shelves is a crucial step of palate development. The opposing shelves adhere to each other at first by adherens junctions, then by desmosomes in the MEE. The MEE seam disappears by epithelial mesenchymal transformation (EMT), which creates confluence of connective tissue across the palate. Cleft palate has a mutifactorial etiology that often includes failure of adherence of apposing individual palatal shelves and/or EMT of the MEE. In this review, we first discuss TGFbeta biology, including functions of TGFbeta isoforms, receptors, down stream transcription factors, endosomes, and signalling pathways. Different isoforms of the TGFbeta family play important roles in regulating various aspects of palate development. TGFbeta1 and TGFbeta2 are involved in growth, but it is TGFbeta3 that regulates MEE transformation to mesenchyme to bring about palatal confluence. Its absence results in cleft palate. Understanding of TGFbeta family signalling is thus essential for development of therapeutic strategies. Because TGFbeta3 and its downstream target, LEF1, play the major role in epithelial transformation, it is important to identify the signalling pathways they use for palatal EMT. Here, we will discuss in detail the mechanisms of palatal seam disappearance in response to TGFbeta3 signalling, including the roles, if any, of growth and apoptosis, as well as EMT in successful MEE adherence and seam formation. We also review recent evidence that TGFbeta3 uses Smad2 and 4 during palatal EMT, rather than beta-Catenin, to activate LEF1. TGFbeta1 has been reported to use non-Smad signalling using RhoA or MAPKinases in vitro, but these are not involved in activation of palatal EMT in situ. A major aim of this review is to document the genetic mechanisms that TGFbeta uses to bring about palatal EMT and to compare these with EMT mechanisms used elsewhere.

Animals↗
PubMed2005

Distinct roles of the ERK pathway in modulating apoptosis of Ras-transformed and non-transformed cells induced by anticancer agent FR901228.

Ectopic expression of oncogenic H-Ras in cells results in increases of cell susceptibility to the anticancer agent FR901228. Investigating the roles of Ras-induced pathways in FR901228-induced apoptosis, we have found that the phosphatidylinositol 3-kinase pathway plays an anti-apoptotic role, whereas the stress-activated protein kinase p38 pathway plays a pro-apoptotic role in FR901228-induced apoptosis. Interestingly, the extracellular signal-regulated kinase (ERK) pathway plays an anti-apoptotic role in non-transformed cells; however, it plays a pro-apoptotic role in Ras-transformed cells in response to FR901228 treatment. An essential role of the ERK pathway in regulating caspase-3 contents may contribute to its pro-apoptotic role in Ras-transformed cells.

Animals↗
PubMed1992

Suppression of transformed phenotype in hybrids of v-fgr and v-raf transformed rat-1 cells with rat embryonic fibroblasts is due to transcriptional inactivation of viral oncogenes.

Rat-1 cells that had been transformed to tumorigenicity by transfection with the retroviral oncogenes v-raf from 3611-murine sarcoma virus, or v-fgr from Gardner-Rasheed feline sarcoma virus were fused with rat embryonic fibroblasts at an early passage. In both fusion experiments hybrid cells were isolated that exhibited normal morphology, anchorage requirement for proliferation, and either no tumorigenicity (v-fgr) or extended latency periods for tumor growth (v-raf) in nude mice. Transcription of viral oncogenes is drastically reduced in hybrid cells (at least 30-fold compared to their transformed parental cells), while the half-life of the corresponding transcripts is not effected. In the chromatin of hybrid cells the integrated retroviral oncogenes are as sensitive to degradation with pancreatic DNase I as the endogenous actin gene. Thus the observed down regulation of proviral transcript levels does not correlate with changes in chromatin structure. We conclude that in hybrids of (v-fgr)- and (v-raf)-transformed Rat-1 cells with embryonic fibroblasts, transcription of the retroviral oncogenes appears to be repressed by trans-acting factors of the normal parental cell.

Animals↗
PubMed2002

Marker-free transformation: increasing transformation frequency by the use of regeneration-promoting genes.

The generation of transgenic plants free of antibiotic resistance markers is a major challenge to plant biologists and plant breeders. Currently, there are two main strategies to achieve this goal: one approach is to excise or segregate marker genes from the host genome after regeneration of transgenic plants, and the second is based on so-called 'marker-free' transformation. Marker-free transformation has been successfully demonstrated by the use of several plant and non-plant genes that are capable of promoting explant regeneration. This approach appears not only to be effective for the generation of marker-free transgenic plants, but also has great potential to improve the transformation frequency of recalcitrant species.

Gene Frequency↗
PubMed2005

Accelerated transformation and deactivation of erythromycin in superheated water. 2. Transformation reactions and bioassays.

The work presented in this second part of a two-part series on the accelerated transformation of erythromycin in superheated water focuses on the chemical nature and resultant antimicrobial implications of the overall reaction observed. Analyses of reactor effluents employing infrared spectroscopy and liquid chromatography/mass spectrometry indicated that the initial step in the decomposition pathway is one of dehydration. Subsequent hydrolysis in the presence of an acetate buffer appeared to result in the loss of the sugar cladinose. Chemical transformation under superheated conditions was tied to the loss of antibiotic function by an agar dilution test. The sensitivity of this test was verified by determination of the minimum inhibitory concentration (MIC) of erythromycin corresponding to each of two test microorganisms. MIC values for the selected strains of Escherichia coli and Bacillus subtilis were 35 and 0.5 mg/L, respectively. To relate the loss of antimicrobial activity to increased reaction temperature and thus to increased extent of parent compound transformation to microbially benign intermediates, bioassays using E. coli as test microorganism were performed on flow reactor effluents resulting from reaction of initial erythromycin concentrations of 75-150 mg/L.

Amino Sugars↗
PubMed1976

Chemical transformation of Chinese hamster cells. I. A comparison of some properties of transformed cells.

Fifty-one subclones from carcinogen-treated cells of 3 tissues (kidney, liver and prostate) of the male Chinese hamster have been studied to determine the relationships of 3 criteria of in vitro transformation: morphological change, increased plating efficiency and growth in soft agar. There was no correlation between increased plating efficiency and the other 2 parameters. Morphological change was not always easily recognisable, particularly in cells derived from liver, and was not always a stable feature of any given subclone. This may be due to the technique of isolation used (ring cloning) or may be due to chemically-treated cells requiring long periods of culturing before attaining a stable phenotype. When a stable morphological appearance was achieved, there was good correlation between transformed morphology and colony formation in soft agar. The problems of scoring morphological change as an assessment of malignant transformation, and the importance of spontaneous morphological changes are discussed.

Benz(a)Anthracenes↗
PubMed1993

Syrian hamster embryo cell lines useful for detecting transforming genes in mouse tumours: detection of transforming genes in X-ray-related mouse tumours.

The Syrian hamster embryo cell lines, SHOK and MC-1, were used as recipient cells for DNA transfection assay to detect transforming genes in experimental mouse tumours. A mouse repeat sequence was utilised to check whether each transformed focus included mouse genomic DNA in the Hamster background. We investigated five mouse tumours that are related to X-ray radiation, and detected activated c-K-ras, c-mos, and c-cot oncogenes which induced foci of hamster cells. These results show that SHOK and MC-1 cells have unique properties for detecting transforming genes in experimental mouse tumours.

3T3 Cells↗
PubMed1991

Regulation of transformation-sensitive secreted phosphoprotein (SPPI/osteopontin) expression by transforming growth factor-beta. Comparisons with expression of SPARC (secreted acidic cysteine-rich protein).

Secreted phosphoprotein I (SPPI; osteopontin), a highly phosphorylated form of which has been associated with cell transformation, is one of the major phosphorylated proteins in bone. Populations of rat bone cells derived from fetal calvariae, neonatal parietal bone and a rat osteosarcoma cell line (ROS 17/2.8) produce several forms of the protein, the major forms having apparent molecular masses of 55 and 44 kDa by SDS/PAGE on 15% (w/v) cross-linked gels and of 60 and 56 kDa on 10% gels. Northern blot analysis of SPPI mRNA using total cellular RNA revealed a single 1.5 kb mRNA species, indicating that the nascent protein chains of these phosphoproteins are identical. On treatment of the cells with transforming growth factor-beta (TGF-beta; 1 ng/ml), the levels of SPPI mRNA and the synthesis of the 55 kDa phosphoprotein, but not of the 44 kDa phosphoprotein, were increased by 1.8-4.5-fold in the normal osteoblastic cells, the stimulation first being evident at 3 h and reaching a maximum at 12 h. In the transformed ROS 17/2.8 cells, TGF-beta did not alter significantly the SPPI mRNA level or the synthesis of either the 55 kDa or the 44 kDa SPPI over the 24 h period studied. By comparison, neither the steady-state levels of SPARC (secreted protein, acidic, rich in cysteine) mRNA nor the synthesis of SPARC protein were affected significantly by the addition of TGF-beta to any of the osteoblastic bone cells. The half-lives for SPPI and SPARC mRNAs in the osteoblastic calvarial cells were calculated to be 18 h and greater than 50 h respectively, in both the presence and the absence of TGF-beta. Since the stability of the mRNA was unchanged by TGF-beta and the increased expression of SPPI mRNA could be blocked by cycloheximide, TGF-beta appears to increase transcription of the SppI gene indirectly by stimulating the synthesis of a protein that promotes transcription. These results demonstrate that several forms of SPPI are synthesized constitutively by bone cells, and that there are clear differences in the regulation of SppI gene expression by TGF-beta in normal bone cells compared with the tumorigenic ROS 17/2.8 cells. The differential responses of normal osteoblastic cells to TGF-beta in the expression of SPPI and the selective stimulation of specific forms of the SPPI protein may be important in bone repair and remodelling.

Animals↗