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PubMed1988

Loss of growth factor dependence and conversion of transforming growth factor-beta 1 inhibition to stimulation in metastatic H-ras-transformed murine fibroblasts.

Cell lines with varying tumorigenic and metastatic potentials have been obtained by transformation of 10T 1/2 fibroblasts using radiation or transfection with T-24 H-ras. We have observed an inverse relationship between metastatic potential and dependence on serum for growth. The effects of basic fibroblast growth factor, platelet-derived growth factor, epidermal growth factor, and transforming growth factor-beta 1 (TGF-beta 1) on these lines were then examined to determine if the changes in the serum dependence of metastatic cells may be due to altered responsiveness to specific growth factors (GFs). Cells were grown in monolayer culture and DNA synthesis was measured by [CH3-3H]thymidine incorporation experiments. Both metastatic and nonmetastatic cells were shown to be equivalent in their diminished responsiveness to basic fibroblast growth factor, platelet-derived growth factor, and epidermal growth factor as compared to their nontransformed, parental 10T 1/2 cells. However, a unique response of metastatic cells to TGF-beta 1 was identified. While TGF-beta 1 inhibited DNA synthesis in 10T 1/2 cells and a nonmetastatic tumor, cells with intermediate to high metastatic ability were stimulated up to 5.8-fold by TGF-beta 1. Interestingly, epidermal growth factor abrogated the TGF-beta 1 inhibition of the parental 10T 1/2 cells, but had no effect on the TGF-beta 1 response of any metastatic line. Therefore, metastatic but not nonmetastatic cells, demonstrated a dramatically altered sensitivity to TGF-beta 1, a response which may be important in determining metastatic potential.

Animals↗
PubMed1988

Transforming growth factor beta 1 positively regulates its own expression in normal and transformed cells.

Transforming growth factor beta 1 (TGF-beta 1) regulates the growth, differentiation, or function of nearly all cell types. We now report that TGF-beta 1 increases steady-state levels of its own message in six different normal and transformed cells in culture. Accumulation of TGF-beta 1 mRNA can be detected by Northern blot analysis within 3 h of addition of the peptide to cells, and enhanced message levels persist as long as TGF-beta 1 is present in the culture medium. This autoinduction is half-maximal at approximately 10 PM TGF-beta 1, and maximal stimulation corresponds to a 2-3-fold increase in transcript levels. In normal rat kidney cells, the rise in TGF-beta 1 mRNA is actinomycin D-sensitive and is accompanied by a parallel (approximately 3-fold) increase in secretion of TGF-beta 1 protein in the culture medium of treated cells, as detected by immunoprecipitation of biosynthetically labeled 35S-labeled TGF-beta 1 using specific anti-TGF-beta 1 antibodies. Treatment of normal rat kidney cells with either epidermal growth factor or platelet-derived growth factor also results in an increase in TGF-beta 1 mRNA (2-3-fold), although epidermal growth factor and TGF-beta 1 appear to act via distinct mechanisms since their combined effects are greater than additive.

Cell Line↗
PubMed1986

[Genetic transformation of somatic cells. X. Morphological transformation and changes in the growth characteristics of NIH 3T3 cells administered the oncogene v-myc].

Transfection of the plasmid containing the cloned gag-myc part of retrovirus MC 29 into mouse NIH 3T3 cells induces focuses of morphological transformation. Isolated morphological transformants have a decreased dependence on serum growth factors, a higher saturation density in monolayer, and an increased cloning efficiency on the glass and in agar. Induced traits are stably inherited, and may constitute the direct consequence of stable maintenance and expression of transfected oncogens.

Animals↗
PubMed1984

Latent beta-transforming growth factor in nontransformed and Kirsten sarcoma virus-transformed normal rat kidney cells, clone 49F.

Normal rat kidney cells of the clone 49F and their Ki-MSV-transformed counterparts spontaneously release the same transforming growth factor (TGF) activity in an inactive form. By acidification followed by neutralization prior to assay, this TGF activity is unmasked and promotes anchorage-independent growth of the NRK-49F indicator cells in the presence of epidermal growth factor. The TGF activity released by both cell types has an apparent molecular weight of 9,000 under acidic conditions, does not compete for binding to epidermal growth factor receptors, is heat resistant but dithiothreitol and trypsin sensitive, and therefore is of the beta-TGF class.

Animals↗
PubMed1993

Up-regulation of transforming growth factor alpha expression by transforming growth factor beta 1, epidermal growth factor, and N,N-dimethylformamide in human colon carcinoma cells.

This report examines the effects of inhibitors of cell proliferation on transforming growth factor alpha (TGF-alpha) expression in low-density cultures of poorly (PD) and well-differentiated (WD) human colon carcinoma cells, continuously maintained in serum-free medium. In contrast to results in certain untransformed cells, growth inhibitors such as transforming growth factor beta 1 (TGF-beta 1) and N,N-dimethylformamide up-regulated TGF-alpha mRNA and protein expression in these human colon carcinoma cells. Treatment of low-density WD cells with TGF-beta 1 (10 ng/ml) resulted in a 1.5-fold increase in TGF-alpha mRNA levels within 4 h of treatment. TGF-alpha mRNA levels increased to 2.7-fold above control values by 48 h after TGF-beta 1 addition. Additionally, over a TGF-beta 1 concentration range of 1-30 ng/ml, TGF-alpha protein levels were increased by 2-10-fold, despite the fact that the growth of the WD cells remained inhibited. Although TGF-beta 1 control of TGF-alpha expression was altered in these WD colon carcinoma cells, relative to that in untransformed cells previously examined, the cells retained the ability to up-regulate TGF-alpha expression in an epidermal growth factor-dependent manner. In similarity to the results with TGF-beta 1 in WD colon carcinoma cells, the differentiation agent N,N-dimethylformamide (0.7%) resulted in an increase of TGF-alpha mRNA of approximately 3.8-fold in PD colon carcinoma cells, as well as a 4.4-fold increase in TGF-alpha protein after 4 days of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Differentiation↗
PubMed1995

Chronic exposure of cultured transformed mouse epidermal cells to transforming growth factor-beta 1 induces an epithelial-mesenchymal transdifferentiation and a spindle tumoral phenotype.

Transformed mouse epidermal keratinocytes of the cell line PDV, when cultured under the presence of transforming growth factor-beta 1 (TGF-beta 1), escaped the block of growth exerted by this factor in normal keratinocytes and underwent marked changes in cell differentiation. TGF-beta 1 induced disruption of epithelial interactions, dispersion of cells, increased local movement, and conversion to a fibroblast-like morphology. These changes were reversible and correlated with down-regulation of epithelial protein markers such as E-cadherin and cytokeratins and upregulation of vimentin. TGF-beta 1-treated cells with a fibroblast-like phenotype induced spindle cell carcinomas upon transplantation in athymic nude mice, whereas untreated PDV cells or fusiform cells reverted to the epithelial phenotype and produced well-differentiated squamous cell carcinomas. Nontumorigenic immortalized epidermal keratinocytes, when grown under the presence of TGF-beta 1, did not transdifferentiate to a mesenchymal phenotype, their proliferation was blocked, and cells finally died. These results suggest a role of TGF-beta 1 in the progression of squamous carcinoma cells to spindle carcinomas in mouse skin carcinogenesis.

Animals↗
PubMed2002

Interaction between the transforming growth factor-beta type II receptor/Smad pathway and beta-catenin during transforming growth factor-beta1-mediated adherens junction disassembly.

The aim of the current study was to examine the influence of transforming growth factor (TGF)-beta 1 on proximal tubular epithelial cell-cell interaction, with particular emphasis on the regulation of adherens junction complex formation. Stimulation of the proximal tubular cell line HK-2 cells by TGF-beta 1 led to loss of cell-cell contact and disassembly of both adherens and tight junctional complexes. Adherens junction disassembly was associated with reduction of both Triton-soluble and Triton-insoluble E-cadherin, and an increase in detergent-soluble beta-catenin. Under these conditions, immunoprecipitation and Western analysis demonstrated decreased association of beta-catenin, both with E-cadherin, alpha-catenin, and the cell cytoskeleton. Confocal microscopy after immunostaining, showed decreased intensity of peripheral E-cadherin staining, and redistribution of beta-catenin expression to a perinuclear location. Tight junction disassembly was manifest by a reduction in the expression of Triton-soluble occludin and ZO-1 by Western analysis and their disassociation manifested by immunostaining and confocal microscopy. Loss of cell-cell contact and disassembly of adherens junctions were seen after addition of TGF-beta 1 to the basolateral aspect of the cells. Immunoprecipitation experiments demonstrated co-localization of E-cadherin, beta-catenin, and TGF-beta 1 RII in unstimulated cells. After TGF-beta 1 stimulation, the TGF-beta 1 RII no longer associated with either E-cadherin or beta-catenin. Dissociation of the adherens junction protein from the TGF-beta 1 receptor was associated with increased beta-catenin tyrosine phosphorylation and decreased threonine phosphorylation. Furthermore after receptor ligand binding, beta-catenin became associated with the TGF-beta 1-signaling molecules Smad3 and Smad4.

Adherens Junctions↗
PubMed1996

Epithelial-mesenchymal transformation of a newly established cell line from ovarian adenosarcoma by transforming growth factor-beta1.

We report on 2 cell lines (designated OVAK-I and OVAK-II) established from an adenosarcoma, a rare variant of a malignant Mullerian mixed tumor, of the ovary. OVAK-I was not tumorigenic in nude mice and showed no responsiveness to transforming growth factor (TGF)-beta1, whereas OVAK-II was tumorigenic and had various biological properties. Light- and electron-microscopic studies showed that the morphology of the cells was converted from an epithelial to a mesenchymal form by TGF-betaI. Furthermore, the protein and mRNA expressions of the epithelial marker carcinoembryonic antigen and the mesenchymal marker vimentin were down- and up-regulated, respectively, by TGF-beta1. These findings suggested that TGF-beta1 plays a role in epithelial-mesenchymal transformation and support the single-stem-cell theory which explains the origin of malignant Mullerian mixed tumors: that the epithelial and mesenchymal components of these tumors are of common stem-cell origin.

Adenosarcoma↗
PubMed2000

Transformation of BALB3T3 cells caused by over-expression of rat CD98 heavy chain (HC) requires its association with light chain: mis-sense mutation in a cysteine residue of CD98HC eliminates its transforming activity.

CD98 is a 125-kDa glycoprotein (GP125) consisting of an 85-kDa heavy chain (HC) and a 40-kDa light chain (LC), and is highly expressed on the cell surface of activated lymphocytes and various tumor cells. In addition to the regulatory role of CD98HC in L-, y(+)L- and Xc-amino-acid transport systems, which are principally mediated by CD98LC, we have reported transforming activity of human CD98HC. In this study, we established and analyzed BALB3T3 clones transfected with cDNAs encoding wild-type and mutated rat CD98HC proteins designated as BrH/Wild, C103S, C325S and 103/325, in which 103 and/or 325 cysteine were intact or replaced with serine. Flow cytometry with anti-rat CD98HC MAb B3 revealed that wild-type and mutated CD98HC transfectants expressed almost the same amounts of rat CD98HC proteins on the cell surface. Immunoprecipitation with B3 revealed that exogenous rat CD98HC proteins were associated with endogenous mouse CD98LC by a disulfide bond in BrH/Wild and C325S, but not in C103S and 103/325 transfectants. These transfectants showed similar doubling times and leucine and arginine transport activities, as compared with BALB3T3 and control transfectants in monolayer culture. Wild-type and C325S transfectants, however, formed much larger anchorage-independent colonies than C103S, 103/325 and control transfectants in soft agar. In addition, wild-type and C325S transfectants showed tumorigenicity in nude mice, although C103S, 103/325 and control transfectants did not. These findings indicate that over-expression of CD98HC and its disulfide-linkage with CD98LC at the cell surface result in malignant transformation of murine fibroblasts.

Amino Acid Substitution↗
PubMed2002

Fourier transform IR and Fourier transform Raman spectroscopy studies of metallothionein-III: amide I band assignments and secondary structural comparison with metallothioneins-I and -II.

The secondary structures of porcine brain Cu(4)Zn(3)-metallothionein (MT)-III and Cd(5)Zn(2)MT-I, Cd(5)Zn(2)MT-II, and Zn(7)MT-I from rabbit livers in the solid state are investigated by Fourier transform IR spectroscopy (FTIR) and Fourier transform Raman spectroscopy (FT-Raman). The Cu(4)Zn(3)MT-III contains 26-28% beta-turns and half-turns, 13-14% 3(10)-helices, 47-49% random coils, and 11-12% beta-extended chains. The structural comparison of porcine brain Cu(4)Zn(3)MT-III with rabbit liver Cd(5)Zn(2)MT-I (II) and Zn(7)MT-I shows that the contents of the random coil structure are obviously increased. The results indicate that the insert of an acidic hexapeptide in the alpha domain of Cu(4)Zn(3)MT-III possibly forms an alpha helix. However, because the bands assigned to the alpha-helix and random coil structures are overlapped in the spectra, the content of random coil structures in Cu(4)Zn(3)MT-III is therefore higher than those in Cd(5)Zn(2)MT-I, Cd(5)Zn(2)MT-II, and Zn(7)MT-I.

Amides↗
PubMed1989

Suppression of focus formation by bovine papillomavirus-transformed cells by contact with non-transformed cells: involvement of sugar(s) and phosphorylation.

Focus formation by bovine papilloma virus-transformed C127 cells was inhibited by direct contact with non-transformed C127 cells. The suppressive capacity of C127 cells was abolished by introduction of the neomycin resistance gene (neor) but not by that of the hygromycin resistance gene (hygrr). Though both genes code for phosphotransferase which inactivates the aminoglycoside antibiotics, their substrates are different, i.e., there is no cross-resistance between them. As the neomycin phosphotransferase phosphorylates the specific hydroxyl group of the sugar in the aminoglycosides, such as 3'OH of the glucose residue of kanamycin A, some specific sugar(s) on the molecules exposed on the cell surface must be responsible for the suppressive signal and their phosphorylation must have resulted in the loss of that signal. The sugar must have the structure shared by kanamycin, neomycin or G418 but not by hygromycin B. Involvement of sugar was also suggested by the observation that concanavalin A partially abrogated the suppressive capacity of C127 cells.

Animals↗
PubMed1993

Effect of serum and cell density on transmembrane distribution of cAMP and cGMP in transformed (C4-I) and non-transformed (WI-38) human cells.

The ratio between cGMP and cAMP in plasma/urine is elevated in several types of malignancies. The present in vitro study showed that the ratio between extracellular cGMP and cAMP increased during the proliferation of C4-I cells (derived from a carcinoma of the uterine cervix), whereas this ratio decreased in WI-38 cells (normal lung fibroblasts). These results can be explained by differences between the transformed and non-transformed cells in the cell-density-dependent transmembrane distribution and intracellular levels of cyclic nucleotides. In the serum-deprived cultures, no profound effects were seen on the cell-density-dependent biokinetics of cAMP and cGMP. In the absence of serum, growth of C4-I cells was markedly retarded, whereas WI-38 cells were unable to expand at all.

Cell Count↗
PubMed1983

Cell growth and differentiation in vitro in mouse macrophages transformed by a tsA mutant of simian virus 40. I. Cellular response in proliferative and phagocytic activities to the shift of temperature differs depending on the culture state in mouse bone marrow cells transformed by the tsA640 mutant of simian virus 40.

It was shown previously that mouse bone marrow cells transformed by simian virus 40 (SV40) show a reversible cell density-dependent phenotypic transition between the nonmacrophage (rapidly growing) and the macrophage (stationary) states; cells in low-density cultures are in the growing phase, express SV40 T antigen strongly as revealed by immunofluorescence, and lose typical macrophage properties such as immune phagocytosis; whereas cells in high-density cultures are in the stationary (nongrowing) phase, express SV40 T antigen weakly, and recover their macrophage properties (Takayama, 1980). In the hope of clarifying the relationship between T antigen, cell growth, and macrophage-specific cellular function, we examined the behavior at 33 and 39 degrees C of mouse bone marrow cells transformed by an SV40 gene A mutant (tsA640) whose mutation renders the molecular weight of 90K (large) T antigen temperature sensitive. The results presented in this paper suggest that functional large T antigen is required for cells in the stationary phase to initiate multiplication when transferred at lower density and is not necessary for a majority of them to maintain the nongrowing state (viability) at both high and lower cell densities, whereas it is required for cells in the growing phase to keep multiplying without losing their viability. The results also suggest that the functional large T antigen does not play a direct role in maintaining the cells as either phagocytic or nonphagocytic. It is also suggested that the physiological or tsA mutation-mediated arrest of growth may or may not be accompanied by induction and/or maintenance of cellular phagocytic activity depending on the culture state.

Animals↗
PubMed1991

Homocysteine export from cells cultured in the presence of physiological or superfluous levels of methionine: methionine loading of non-transformed, transformed, proliferating, and quiescent cells in culture.

Determination of the transient increase in plasma homocysteine following administration of excess methionine is an established procedure for the diagnosis of defects in homocysteine metabolism in patients. This so-called methionine loading test has been used for 25 years, but the knowledge of the response of various cell types to excess methionine is limited. In the present paper we investigated homocysteine export from various cell types cultured in the presence of increasing concentrations (15-1,000 microM) of methionine. For comparison of homocysteine export, the export rates per million cells were plotted versus cell density for proliferating cells, and versus time for quiescent cells. The homocysteine export from growing cells was greatest during early to mid-exponential growth phase, and then decreased as a function of cell density. The export rate was higher from phytohemagglutinin-stimulated than non-stimulated lymphocytes, and higher from proliferating than from quiescent fibroblasts. The hepatocytes showed highest export rate among the cell types investigated. The enhancement of homocysteine export by excess methionine ranged from no stimulation to marked enhancement, depending on cell type investigated, and three different response patterns could be distinguished: 1) quiescent fibroblasts and growing murine lymphoma cell showed no significant increase in homocysteine export following methionine loading; export from human lymphocytes was only slightly enhanced in the presence of excess methionine; 2) the homocysteine export from proliferating hepatoma cells and benign and transformed fibroblasts was stimulated three to eightfold by increasing the methionine concentration in the medium from 15 to 1,000 microM; and 3) the response to methionine loading was particularly increased (about 15-fold) in non-transformed primary hepatocytes in stationary culture. The results outline a potentially useful procedure for the comparison of homocysteine export during cell growth in the presence of various concentrations of methionine. The results are discussed in relation to the special feature of homocysteine metabolism in various cell types and tissues including liver, and to the possible source of plasma homocysteine following methionine loading in vivo.

Animals↗
PubMed1992

Variable alpha-tocopherol stimulation and protection of glutathione peroxidase activity in non-transformed and transformed fibroblasts.

Studies on glutathione metabolism in an established baby hamster kidney cell line (BHK-21/C13) and in its polyoma virus-transformed counterpart (BHK-21/PyY), have revealed a significant stimulation of intracellular glutathione peroxidase activity (Se-independent plus Se-dependent) by alpha-tocopherol supplementation (14 microM). This stimulation was found to be much greater in the transformed cells. Other GSH-requiring enzyme activities (namely glutathione reductase and glutathione transferase) were unaltered by alpha-tocopherol treatment, suggesting a degree of specificity in its action on GSHpx. In unsupplemented growth media, the GSHpx activity in both cell lines was significantly decreased by an oxidative stress. However, the same stress applied to the alpha-tocopherol-supplemented cells had no effect on the stimulated GSHpx activity, suggesting a protection afforded by the alpha-tocopherol.

Animals↗
PubMed1975

Demonstration of infectious DNA in transformed cells. II. Characterization of uptake of SV40-transformed mouse cell DNA by simian cells.

The initial steps in the DNA-transfer, or transfection, method of virus rescue were characterized using primary green monkey (GMK) cells exposed to SV40-transformed mouse (SV-3T3) cell DNA in the presence of 1 mg/ml DEAE-dextran. When large amounts (10-50mug) of high molecular weight DNA (greater than 10(7) daltons) were inoculated onto 10(6) GMK cells, usually less than 1 mug became cell-associated. DNA fragmented to a size of 1-3 X 10(6) daltons was bound more efficiently by the recipient cells, but generally only 5-10 per cent of the inoculum (representing 1-4 mug) was taken up. Approximately 50 per cent of the cell-associated DNA had penetrated to a DNase-resistant state by the end of the 30-minute incubation period. The effect of the size of thr transformed cell DNA molecule on the recovery of SV40 in transfection experiments was investigated. The trend appeared to be that rescue was more efficient with the larger molecular weight samples.

Animals↗
PubMed1996

Regulation of complement C3 synthesis by interleukin-1 and transforming growth factor-beta in rat non-transformed intestinal epithelial cell line, IEC-6.

Intestinal epithelial cells are an important source of many biologically active molecules that modulate immune responses in the mucosa. The purpose of this study was to demonstrate the synthesis of complement C3 component in the rat non-transformed crypt-like intestinal epithelial cell line, IEC-6. Unstimulated IEC-6 cells secreted a low level of C3 protein and showed weak expression of C3 mRNA. The addition of interleukin (IL)-1 beta induced a dose- and time-dependent increase in C3 production. These effects of IL-1 beta were observed at a concentration as low as 0.01 ng/ml and reached a plateau at a concentration of 5 ng/ml. The effects were observed at the mRNA level as early as 6 h after the beginning of incubation. Transforming growth factor (TGF)-beta alone had no effect. However, TGF-beta at low concentrations (0.001-1 ng/ml) enhanced the effect of IL-1 beta in increasing C3 production; this enhancement was not observed at high concentrations (5-10 ng/ml). These effects of TGF-beta were also observed at the mRNA level. The present findings indicate that intestinal epithelial cells are indeed capable of synthesizing complement C3 in response to IL-1 beta and TGF-beta.

Animals↗