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PubMed1998

Histologic and immunophenotypic features prior to transformation in patients with transformed cutaneous T-cell lymphoma: is CD25 expression in skin biopsy samples predictive of large cell transformation in cutaneous T-cell lymphoma?

Large cell transformation (LCT) in cutaneous T-cell lymphoma (CTCL) is estimated to occur up to approximately 20% of patients. This morphologic change is associated with aggressive behavior and shortened survival. Our purpose was to identify morphologic and/or immunophenotypic features in CTCL skin biopsies that are predictive of transformation. We analyzed 12 cases of CTCL (three cases of mycosis fungoides and nine cases of Sezary syndrome) that underwent LCT and for which sequential biopsies before and after transformation were available. Eight of 12 cases had pre-LCT marker studies performed on frozen tissue. The histologic and immunophenotypic features of CTCL and LCT were reviewed. Morphologically, CTCL biopsies showed the following: Pautrier microabscesses (five cases), epidermotropism of single lymphoid cells (three cases), and nonspecific histology (four cases). Immunophenotyping prior to transformation showed aberrant loss of T-cell markers (CD5, CD7, CD5 and CD7) in three of eight cases. CD4:CD8 ratios were increased in all cases. Expression of CD25 by the neoplastic lymphoid cells was detected in six of seven cases. LCT immunophenotyping showed additional loss of CD7 in one of five cases and of CD25 in three of five cases. In conclusion, expression of CD25 in CTCL may identify a subset of patients at risk of undergoing LCT.

Adult↗
PubMed2006

Ring-B functionalized androst-4-en-3-ones and ring-C substituted pregn-4-en-3-ones undergo differential transformation in Aspergillus tamarii KITA: ring-A transformation with all C-6 substituted steroids and ring-D transformation with C-11 substituents.

The fungus Aspergillus tamarii transforms progesterone 1 into testololactone 5 in high yield through a four-step enzymatic pathway which is flexible to a range of steroidal substrates. To date, no studies have investigated the fate of C-6 (ring-B) and C-11 (ring-C) functionalized steroidal substrates on metabolism. Remarkably all of the C-6 functionalized substrates underwent reductive metabolism on ring-A in contrast to C-11 functionalized steroids where only ring-D oxidative or reductive transformation occurred. In order to discern the precise role of the functional groups in directing metabolism 6-ketoprogesterone 10 with functionality at C-6 and the ring-D methyl ketone underwent reductive and oxidative transformation on both terminal A and D rings showing that this functionality was directing metabolism. Androst-4-en-3,6-dione 12 devoid of ring-D functionality underwent reductive metabolism on ring-A proving that the C-6 functionality was directing metabolism to this ring with the ring-D methyl ketone responsible for generating transformation at this position. Functionality at C-11 exclusively controlled entry into and degree of metabolism on the lactonization pathway. These novel findings may have important bearing in the future understanding of structure activity relationships in revealing new metabolic pathways and further affords a unique opportunity for generation of novel bioactive steroidal compounds.

Androstenes↗
PubMed1989

Growth stimulation, altered regulation of epidermal growth factor receptors, and autocrine transformation of spontaneously transformed normal rat kidney cells by transforming growth factor beta.

The tumorigenic NRK-PT14 cell line requires exogenous epidermal growth factor (EGF), but has lost the requirement for transforming growth factor beta (TGF-beta) for anchorage-independent growth, compared to normal rat kidney (NRK) cells. Development of an optimized serum-free medium for the growth of these cells revealed that NRK-PT14 cells also exhibit a qualitatively altered sensitivity to exogenous type 1 TGF-beta, compared to NRK cells. EGF-induced serum-free monolayer growth of NRK-PT14 cells was stimulated 2-fold by TGF-beta under conditions where growth of NRK cells was inhibited by 67%. TGF-beta only stimulated the growth of NRK-PT14 cells when EGF was present and when EGF was added before TGF-beta. In addition, the stimulation of EGF-induced NRK-PT14 cell growth by TGF-beta was associated with a specific, reversible loss of the high-affinity subpopulation of EGF receptors from the surface of these cells. Treatment of NRK cells with TGF-beta resulted in an increase in this EGF receptor population. Finally, EGF-induced anchorage-independent growth of NRK-PT14 cells was shown to be dependent on secreted TGF-beta, demonstrating an autocrine role for TGF-beta in the transformed phenotype of these cells. Autocrine transformation of NRK-PT14 cells by TGF-beta may result directly from the acquisition of an altered (positive) sensitivity to this growth factor.

Animals↗
PubMed1978

Expression of transformation in cell hybrids. II. Nonsuppression of the transformed phenotype in hybrids between a chemically transformed and nontransformed derivatives of Balb/3T3.

Hybrid clones derived from a nitrosocarbaryl-transformed Balb/3T3 cell line, Clone H, and a nontransformed cell line THO2 resemble the transformed parent in the clone morphology, higher saturation density, colony formation in medium with reduced serum concentration, growth in agarose and ability to form clones on Balb/3T3 monolayer. Results are discussed in the framework of genetic models which permit or require dominant mutations for the expression of transformed phenotype.

Animals↗
PubMed1985

Transforming growth factors from a human tumor cell: characterization of transforming growth factor beta and identification of high molecular weight transforming growth factor alpha.

Intracellular transforming growth factors (TGFs) were extracted from a human rhabdomyosarcoma cell line and purified to apparent homogeneity by using gel filtration, cation-exchange, and high-performance liquid chromatography. Two types of transforming growth factor activities, TGF-alpha and TGF-beta, were detected. The intracellular polypeptides which belonged to the TGF-alpha family required TGF-beta for full activity in inducing nonneoplastic normal rat kidney fibroblasts to grow in soft agar. These peptides also bound to the membrane receptor for epidermal growth factor. As determined by sodium dodecyl sulfate-polyacrylamide gels, the apparent molecular weight of these intracellular TGF-alpha's was 18 000. Intracellular TGF-beta required either epidermal growth factor or TGF-alpha for stimulation of soft agar growth. The intracellular TGF-beta was purified to homogeneity as judged by a single peak after reverse-phase high-performance liquid chromatography and a single band on a sodium dodecyl sulfate-polyacrylamide gel. The intracellular TGF-beta from the human tumor cell line was similar in all respects tested (migration on sodium dodecyl sulfate-polyacrylamide gels, stimulation of soft agar growth, binding to the membrane receptor for TGF-beta, and amino acid composition) to intracellular TGF-beta from normal human placenta.

Amino Acids↗
PubMed1993

Transforming growth factor-beta 1 induces transforming growth factor-alpha promoter activity and transforming growth factor-alpha secretion in the human colon adenocarcinoma cell line FET.

FET cells are well differentiated human adenocarcinoma cells whose growth is partially inhibited (50-60%) by transforming growth factor-beta 1 (TGF-beta 1). In exponentially growing cultures, TGF-beta 1 induces the expression of transforming growth factor-alpha (TGF-alpha) by 3-fold. To determine whether this induction is the result of increased TGF-alpha promoter activity, FET cells were transiently transfected with a plasmid containing 2816 base pairs of the 5'-flanking region of the TGF-alpha gene linked to luciferase. Transfected FET cells treated with growth-inhibitory concentrations of TGF-beta 1 (10 ng/ml) showed up to a 10-fold increase in luciferase activity. The increase in luciferase activity was dose dependent through the normal physiological range of TGF-beta 1 (0.5-20 ng/ml), saturating at 10 ng/ml. This effect was also TGF-alpha promoter specific, inasmuch as the Rous sarcoma virus long terminal repeat used as a control remained relatively insensitive to the effects of TGF-beta 1. By using progressively smaller portions of the TGF-alpha promoter region, the TGF-beta 1-responsive element was mapped between base pairs -77 and -201 of the 5'-flanking region. TGF-beta 1 treatment also affected epidermal growth factor receptor levels. FET cells treated with TGF-beta 1 (10 ng/ml) for 48 h showed a 20% decrease in the number of epidermal growth factor receptors and a 2-fold increase in the number of high affinity epidermal growth factor receptors on their surface. These results indicate that TGF-beta 1 acts as a positive regulator of TGF-alpha transcription, and they suggest a possible mechanism by which these cells circumvent the growth-inhibitory effects of TGF-beta 1.

Adenocarcinoma↗
PubMed1986

Assessment of biological activity of linear alpha-transforming growth factor and monospecific antibodies to alpha-transforming growth factor and linear alpha-transforming growth factor.

alpha-Transforming growth factors (TGFs) are low-molecular-weight polypeptides (Mr 5000-7000) which are secreted by a variety of human cancer cells in vitro. Their presence has also been reported in the urine of patients with malignancies, human tumor extracts, and in the conditioned medium of primary human tumor cell cultures. There is evidence that alpha-TGFs bind to membrane receptors of the secreting cells, thus stimulating cell growth in a positive feedback manner (autocrine secretion). We have used a synthetic linear alpha-TGF to study the biological activity of affinity-purified polyclonal sheep antibodies against the carboxyterminal part (17 amino acids) of synthetic rat alpha-TGF. The antigen was found to bind to epidermal growth factor receptors of target cells and to stimulate soft agarose colony formation of normal fibroblasts. Although the antibodies recognized the linear alpha-TGF molecule, they did not inhibit the binding to epidermal growth factor receptors. The antibodies also failed to inhibit alpha-TGF-stimulated colony formation of normal rat fibroblasts. In addition, essentially no cytotoxic activity of the antibodies was found against 41 fresh human tumor specimens in a human tumor cloning assay. Antibodies against the complete alpha-TGF molecule should be used in further attempts to interfere with the autocrine secretion of transforming growth factors.

Animals↗
PubMed2000

Mechanisms of cell transformation in the Syrian hamster embryo (SHE) cell transformation system.

The Syrian hamster embryo (SHE) cell transformation system has been used for investigational studies of basic mechanisms of neoplastic transformation, as well as determining the carcinogenic potential of chemical, physical, and biological agents. Many of these investigations utilize an intermediate step in the SHE cell neoplastic transformation process, known as morphological transformation, as an indicator that the cells have acquired an increased potential to progress to malignancy. While the nature of the morphologically transformed phenotype is not completely understood, it is believed to result from a block in the cellular differentiation of stem cells present within the SHE cell population. In terms of determination of the transforming potential of biological/chemical/physical agents, more than 500 agents have been tested in the SHE cell transformation assay with an 80-90% correlation between MT and carcinogenic potential. As such, the SHE cell transformation assay has utility as a test to provide short-term information on the carcinogenic potential of chemicals. One class of agents of current interest with regard to SHE cell transformation assay utilization consists of growth and differentiation factors (GDFs). Analysis of the SHE cell transformation potential of the GDFs, epidermal growth factor (EGF), fibroblast growth factor 4 (FGF-4), platelet-derived growth factor AA (PDGF AA), PDGF AB, PDGF BB, and the antimitogenic GDF, transforming growth factor beta one (TGF-beta1), was performed. All GDFs, with the exception of TGF-beta1, induced SHE cell transformation. However, an interesting difference between the GDFs was observed--PDGF A/B and PDGF B/B, but not PDGF A/A, EGF, or FGF-4, induced transformation after both a transient 1-day exposure and a continuous 7-day exposure, while continuous 7-day exposure was required for transformation by PDGF A/A, EGF, and FGF-4. Interestingly, both transient 1-day and continuous 7-day TGF-beta1 exposure resulted in suppression of transformation induced by a variety of transforming agents including growth factors, Ames assay-positive carcinogens, Ames assay-negative carcinogens, and spontaneous transformation. Interestingly TGF-beta1 was not able to suppress transformation by the tumor promoter, TPA. Together, these data demonstrate the utility of the Syrian hamster embryo cell transformation system for analyzing the transforming potential of GDFs and for characterizing differences in transforming mechanisms between different GDFs.

Animals↗
PubMed1994

Growth suppression of transformed BALB/c 3T3 cells by transforming growth factor beta 1 occurs only in the presence of their normal counterparts.

Transforming growth factor beta 1 (TGF-beta 1) enhances the yield of transformed foci of BALB/c 3T3 cells, but the continuous presence of TGF-beta 1 after foci formation inhibits the growth of transformed foci. The focus-forming ability of Ha-ras-, v-src- and PyMT-transformed cells growing on a monolayer of non-transformed cells was completely suppressed by TGF-beta 1, whereas growth of the transformed cells was little inhibited by TGF-beta 1 in the absence of their normal counterparts. The inhibition by TGF-beta 1 of focus formation by transformed BALB/c 3T3 cells on a normal cell monolayer remained when TGF-beta 1 was removed from the culture medium after 2 weeks. However, the transformed cells were not killed, since they grew in culture conditions under which only transformed cells are able to grow (soft agar). These results suggest that TGF-beta 1 suppresses growth of transformed cells in the presence of normal cells. Furthermore, when non-transformed cells were treated with TGF-beta 1 before co-culture with Ha-ras-transformed cells, formation of transformed foci was inhibited. When normal and transformed cells were cultured in the same dish but separated physically, focus formation was still inhibited. On the other hand, TGF-beta 1 enhanced the growth and changed the morphology of non-transformed cells only in the presence of transformed counterparts. The growth inhibitory effect of TGF-beta 1 on transformed cells and its growth stimulatory effect on non-transformed cells in co-culture conditions suggest the induction of reciprocal paracrine growth regulatory factors. As TGF-beta 1 inhibits the growth of transformed BALB/c 3T3 cells only in the presence of their normal counterparts, a paracrine negative growth control mechanism appears to be operating.

3T3 Cells↗
PubMed1980

Temperature dependency for maintenance of transformation in mouse cells transformed by simian virus 40 tsA mutants.

Mouse embryo fibroblasts and 3T3 cells were transformed by wild-type, tsB4, tsA7, tsA58, and tsA209 simian virus 40. Clones of transformants were generated both in soft agar and in liquid medium by focus formation and at both high and relatively low multiplicities of infection. All transformants were assayed for three phenotypes of transformation: (i) the ability to form highly multinucleated cells in cytochalasin B-supplemented medium, i.e., uncontrolled nuclear division; (ii) the capacity to continue DNA synthesis at increasing cell density; and (iii) the ability to form colonies in soft agar. The great majority of mouse embryo fibroblast transformants generated with tsA mutant virus were temperature sensitive for transformation in all three assays, regardless of the input multiplicity or whether they were generated in liquid medium or soft agar. These transformants exhibited a normal or near-normal phenotype at the nonpermissive temperature of 40 degrees C. All but one of the transformants which appeared transformed at both temperatures were in the A209 group. In contrast to mouse embryo fibroblasts, transformants generated with 3T3 cells and tsA virus were often not temperature sensitive, exhibiting the transformation phenotypes at both temperatures. This phenomenon was more often observed when 3T3 transformants were generated in soft agar. These results, along with other published data, suggest that uncontrolled nuclear division and uncontrolled DNA synthesis are a function of the simian virus 40 A gene. Finally, with the 3T3 transformants, there was often discordance in the expression of transformation among the three phenotypes. Some tsA transformants were temperature sensitive in one of two assays but were transformed at both 33 and 40 degrees C in the remaining assay(s). Other transformants exhibited a normal cytochalasin B response at either temperature but were temperature sensitive in the other assays.

Animals↗
PubMed1990

Natural plasmid transformation in a high-frequency-of-transformation marine Vibrio strain.

The estuarine bacterium Vibrio strain DI-9 has been shown to be naturally transformable with both broad host range plasmid multimers and homologous chromosomal DNA at average frequencies of 3.5 X 10(-9) and 3.4 X 10(-7) transformants per recipient, respectively. Growth of plasmid transformants in nonselective medium resulted in cured strains that transformed 6 to 42, 857 times more frequently than the parental strain, depending on the type of transforming DNA. These high-frequency-of-transformation (HfT) strains were transformed at frequencies ranging from 1.1 X 10(-8) to 1.3 X 10(-4) transformants per recipient with plasmid DNA and at an average frequency of 8.3 X 10(-5) transformants per recipient with homologous chromosomal DNA. The highest transformation frequencies were observed by using multimers of an R1162 derivative carrying the transposon Tn5 (pQSR50). Probing of total DNA preparations from one of the cured strains demonstrated that no plasmid DNA remained in the cured strains which may have provided homology to the transforming DNA. All transformants and cured strains could be differentiated from the parental strains by colony morphology. DNA binding studies indicated that late-log-phase HfT strains bound [3H]bacteriophage lambda DNA 2.1 times more rapidly than the parental strain. These results suggest that the original plasmid transformation event of strain DI-9 was the result of uptake and expression of plasmid DNA by a competent mutant (HfT strain). Additionally, it was found that a strain of Vibrio parahaemolyticus, USFS 3420, could be naturally transformed with plasmid DNA. Natural plasmid transformation by high-transforming mutants may be a means of plasmid acquisition by natural aquatic bacterial populations.

DNA, Bacterial↗
PubMed1993

Transforming growth factor-alpha expression during liver regeneration after partial hepatectomy and toxic injury, and potential interactions between transforming growth factor-alpha and hepatocyte growth factor.

Transforming growth factor-alpha and hepatocyte growth factor are important stimulators of hepatocyte proliferation. In this series of experiments we sought to measure the expression of transforming growth factor-alpha mRNA by hepatocytes in response to toxic liver injury produced by carbon tetrachloride or galactosamine and to perform a more detailed analysis of transforming growth factor-alpha expression after partial hepatectomy. We also explored the interactions of transforming growth factor-alpha and hepatocyte growth factor in their effects on hepatocytes in vitro and tested the ability of these factors to stimulate endogenous transforming growth factor-alpha production by hepatocytes. In previous work we have used oligonucleotide probes to measure transforming growth factor-alpha mRNA expression after partial hepatectomy. In this study we used a rat transforming growth factor-alpha cDNA probe and found that the level of liver transforming growth factor-alpha mRNA increases 4 hr after partial hepatectomy, shows peak expression at 18 hr and returns to the normal level by 36 to 48 hr. Measurement of the corresponding peptide in the liver by means of radioimmunoassay shows that the level of transforming growth factor-alpha rises by 12 hr, peaks at 24 hr and remains significantly increased at 48 hr compared with the levels in sham-operated rats. Carbon tetrachloride and galactosamine are known to produce different patterns of acute liver injury, with maximal hepatocyte DNA synthesis at 48 hr and 5 days, respectively. After carbon tetrachloride administration the profiles of the transforming growth factor-alpha and hepatocyte growth factor mRNA expression are similar, each showing two peaks: the first at 12 hr and the second at 48 hr. In contrast, after galactosamine-induced liver injury the expression patterns of transforming growth factor-alpha and hepatocyte growth factor mRNAs differ: hepatocyte growth factor shows a major peak at 24 hr, with a smaller increase at 5 days, whereas transforming growth factor-alpha begins to increase after 2 days, with a single peak occurring at 5 days. In primary hepatocyte cultures, transforming growth factor-alpha and hepatocyte growth factor appear to have complementary effects. The maximal hepatocyte nuclear labeling index induced by hepatocyte growth factor was 42%; the addition of transforming growth factor-alpha increased this to 74%. Exogenous transforming growth factor-alpha, but not hepatocyte growth factor, stimulates the production of the transforming growth factor-alpha peptide by hepatocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Mitogenic and antimitogenic transforming growth factors secreted by adenovirus 2- and simian virus 40-transformed hamster cells: possible roles in promoting tumorigenesis.

Adenovirus 2 (Ad2)- and simian virus 40 (SV40)-transformed hamster embryo cells differ markedly in a number of phenotypic properties including their potential for inducing tumors in hamsters. Both Ad2- and SV40-transformed cells are immortalized and readily induce tumors in immunoincompetent newborn syngeneic hamsters, but only SV40-transformed cells are highly oncogenic in both adult syngeneic and allogeneic immunocompetent hamsters. The reasons for the difference in the oncogenic potential of the Ad2- and SV40-transformed phenotypes remain elusive. However, recent studies with transforming growth factors (TGFs) indicate that these factors play an important role in determining many phenotypic characteristics of transformed cells. To determine whether TGFs secreted by Ad2- and SV40-transformed hamster embryo cells differ, we have examined the ability of media conditioned by these two transformed cell phenotypes to modulate thymidine uptake in quiescent, untransformed cells. We found that both transformed phenotypes secrete very similar TGF alpha-like mitogenic factors which inhibit binding of 125I-labeled epidermal growth factor to its receptor. Our results also show that SV40-transformed cells, but not Ad2-transformed cells, secrete a powerful mitogenic inhibitor (MI). The MI secreted by SV40-transformed cells is inhibitory for several transformed and untransformed cell types and exerts a cytostatic, not cytolytic, action on untransformed primary hamster embryo cells. MI elutes from size exclusion high-performance liquid chromatography columns with a molecular weight of 24,000. Although MI has about the same molecular weight as TGF beta, it differs from TGF beta in two important respects: it is heat labile and it has a different target specificity for antimitogenic activity. The MI secreted by SV40-transformed cells also inhibits thymidine uptake by concanavalin A-stimulated spleen lymphocytes. This finding suggests that MI might contribute to the extreme oncogenicity of SV40-transformed cells by inhibiting mobilization of immune effector cells at the site of tumor cell proliferation.

Adenoviridae↗
PubMed1987

Distinctive transforming genes in x-ray-transformed mammalian cells.

DNAs from hamster embryo cells and mouse C3H/10T1/2 cells transformed in vitro by x-irradiation into malignant cells transmit the radiation transformation phenotype by producing transformed colonies (transfectants) in two mouse recipient lines, the NIH 3T3 and C3H/101/2 cells, and in a rat cell line, the Rat-2 cells. DNAs from unirradiated cells or irradiated and visibly untransformed cells do not produce transformed colonies. The transfectants grow in agar and form tumors in nude mice. Treatment of the DNAs with restriction endonucleases prior to transfection indicates that the same transforming gene (oncogene) is present in each of the transformed mouse cells and is the same in each of the transformed hamster cells. Southern blot analysis of 3T3 or Rat-2 transfectants carrying oncogenes from radiation-transformed C3H/10T1/2 or hamster cells indicates that the oncogenes responsible for the transformation of 3T3 cells are not the Ki-ras, Ha-ras, or N-ras genes, nor are they neu, trk, raf, abl, or fms, although quick blot analysis using 11 oncogene probes detected increased transcripts of c-abl and c-fms in the 3T3 transformants containing oncogenic sequences from the x-ray-transformed C3H/10T1/2 cells. The work demonstrates that DNAs from mammalian cells transformed into malignancy by direct exposure in vitro to radiation contain genetic sequences with detectable transforming activity in three recipient cell lines. The results provide evidence that DNA is the target of radiation carcinogenesis induced at a cellular level in vitro. The experiments indicate that malignant radiogenic transformation in vitro of hamster embryo and mouse C3H/10T1/2 cells involves the activation of unique non-ras transforming genes, which heretofore have not been described.

Animals↗
PubMed1999

Analysis of the Transforming Potential of Growth and Differentiation Factors in Syrian Hamster Embryo Cells: Reversible and Irreversible Transformation.

The mitogenic growth and differentiation factor (GDFs) oncostatin M (OM), epidermal growth factor (EGF), fibroblast growth factor 4 (FGF-4), platelet-derived growth factor AA (PDGF AA), PDGF AB, and PDGF BB and the anti-mitogenic GDF, transforming growth factor beta one (TGF-beta1), were tested in the 7-day continuous exposure and 24-h transient exposure Syrian hamster embryo (SHE) cell transformation assay to determine their reversible and irreversible transforming potential. OM was negative while EGF, FGF-4, and PDGF AA were positive for statistically significant morphological transformation (MT) in the 7-day exposure SHE cell transformation assay. PDGF AB and PDGF BB (but not EGF, FGF-4, and PDGF AA) were positive for statistically significant MT in the 24-h transient exposure SHE cell transformation assays. TGF-beta1 was not only negative for the induction of MT in the 7-day and 24-h exposure SHE cell transformation assays, but suppressed the spontaneous background transformation response. Investigation of the transformation suppression potential of TGF-beta1 demonstrated that TGF-beta1 was able to irreversibly suppress the transformation potential of a variety of transforming agents including growth factors, Ames assay positive carcinogens, and Ames assay negative carcinogens. PDGF AA and PDGF BB were investigated to better understand the reversible and irreversible transformation response. Differences in the receptors activated, the proteins phosphorylated by the receptors, and immediate early gene expressed were observed in SHE cells treated with either PDGF AA or PDGF BB. Importantly, SHE cells treated with TGF-beta1 and PDGF BB, two GDFs, which modulate SHE cell transformation irreversibly, altered DNA methylation; PDGF AA did not demonstrate this effect. Together these data demonstrate that the SHE cell transformation assay can be utilized to evaluate the transformation potential and mechanism of activation of GDFs.

Journal Article↗
PubMed1978

Transformation of BALB/c-3T3 cells by tsA mutants of simian virus 40: temperature sensitivity of the transformed phenotype and retransofrmation by wild-type virus.

The function of the A gene of simian virus 40 (SV40) in transformation of BALB/c-3T3 cells was investigated by infecting at the permissive temperature with wild-type SV40 and with six tsA mutants whose mutation sites map at different positions in the early region of the SV40 genome. Cloned transformants were then characterized as to the temperature sensitivity of the transformed phenotype. Of 16 tsA transformants, 15 were temperature sensitive for the ability to overgrow a monolayer of normal cells, whereas three of three wild-type transformants were not. This pattern of temperature sensitivity of the transformed phenotype was also observed when selected clones were assessed for the ability to grow in soft agar and in medium containing low concentration of serum. The temperature resistance of the one exceptional tsA transformant could be attributed neither to the location of the mutation site in the transforming virus nor to transformation by a revertant virus. This temperature-resistant tsA transformant, however, was demonstrated to contain a higher intracellular concentration of SV40 T antigen than a temperature-sensitive line transformed by the same tsA mutant. A tsA transformant displaying the untransformed phenotype at the nonpermissive temperature was found to be susceptible to retransformation by wild-type virus at this temperature, demonstrating that the temperature sensitivity of the tsA transformants is due to the viral mutation and not to a cellular defect. These results indicate that continuous expression of the product of the SV40 A gene is required to maintain the transformed phenotype in BALB/c-3T3 cells.

Animals↗
PubMed1994

Expression of transforming growth factor-beta 1 messenger ribonucleic acid and the modulation of deoxyribonucleic acid synthesis by transforming growth factor-beta 1 in human endometrial cells.

OBJECTIVE: The purpose of this study was (1) to evaluate the potential sites of transforming growth factor-beta 1 synthesis in human endometrium by analyzing separated endometrial glands and stromal cells for transforming growth factor-beta 1 messenger ribonucleic acid by Northern analysis of total ribonucleic acid and (2) to investigate the effects of transforming growth factor-beta 1 on deoxyribonucleic acid synthesis in endometrial epithelial and stromal cells in culture. STUDY DESIGN: Endometrial glands and stroma from proliferative and secretory endometrium were isolated after collagenase treatment of endometrial tissue minces and were analyzed for transforming growth factor-beta 1 messenger ribonucleic acid by Northern analysis. We studied the effects of estradiol-17 beta and transforming growth factor-beta 1 on deoxyribonucleic acid synthesis in endometrial epithelium and transforming growth factor-beta 1 on stromal cells in culture by evaluating tritiated thymidine incorporation into trichloroacetic acid-precipitable material. RESULTS: Transforming growth factor-beta 1 messenger ribonucleic acid was detected for Northern analysis in separated endometrial stromal cells in levels that were greatest during the secretory phase and in greater levels than in epithelial cells from that same tissue. Transforming growth factor-beta 1 messenger ribonucleic acid in glandular epithelium in culture was not increased to detectable levels by treatment with transforming growth factor-beta 1. Deoxyribonucleic acid synthesis in endometrial glandular epithelium was inhibited by transforming growth factor-beta 1, but transforming growth factor-beta 1 stimulated deoxyribonucleic acid synthesis in endometrial stromal cells in culture. After treatment for 5 days with estradiol-17 beta (10(-8) mol/L), deoxyribonucleic acid synthesis in endometrial glands in culture was decreased by 40%. Transforming growth factor-beta 1 (1 ng/ml) did not alter this effect of estradiol-17 beta on deoxyribonucleic acid synthesis. CONCLUSIONS: Transforming growth factor-beta 1 acts to decrease deoxyribonucleic acid synthesis in epithelial cells and to increase it in stromal cells isolated from human endometrium and maintained in monolayer culture. Transforming growth factor-beta 1, potentially of stromal cell origin, could participate in the regulation of endometrial cell proliferation and differentiation in vivo.

Cells, Cultured↗