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PubMed1987

Transformation by the oncogene v-fms: the effects of castanospermine on transformation-related parameters.

The effects of castanospermine on various parameters associated with transformation were examined in cells expressing the viral oncogene v-fms. Fischer rat embryo (FRE) cells transformed by the oncogene v-fms and grown in the presence of castanospermine reverted to a more normal cell morphology and accumulated fms protein within the endoplasmic reticulum. Treated cells attained contact inhibition of cell growth at a much lower cell density compared to the untreated controls. No effect of castanospermine on cell growth was observed for FRE cells transformed by a different oncogene v-fgr. Castanospermine-treated SM-FRE (v-fms transformed) cells reexpressed extracellular matrix fibronectin and exhibited an extensive actin-containing cytoskeleton similar to that of normal nontransformed FRE cells. Castanospermine treatment of SM-FRE cells resulted in a sixfold decrease in [3H]deoxyglucose uptake compared to that of the nonreverted SM-FRE cells. Again, no effect was observed in FRE cells transformed by the oncogene v-fgr (GR-FRE). These results further characterize the reversion caused by castanospermine and indicate that cell surface expression coordinately controls anchorage independent growth, cell morphology, contact inhibition of growth, and hexose uptake.

Actins↗

PubMed2004

Down-regulation of SHP1 and up-regulation of negative regulators of JAK/STAT signaling in HTLV-1 transformed cell lines and freshly transformed human peripheral blood CD4+ T-cells.

Adult T-cell leukemia (ATL) is an aggressive malignancy that is associated with human T-cell lymphotropic virus I (HTLV-I) infection. HTLV-I transformed T-cell lines and fresh ATL cells are characterized by constitutive activation of the interleukin-2 receptor (IL-2R) signaling pathway however, the mechanism(s) responsible for constitutive IL-2R activation are unknown. To further examine the cause of this signaling pathway deregulation, we measured mRNA and protein expression levels by real-time PCR and Western blots, respectively, of four negative regulators of the IL-2R signaling pathway including src homology 2 (SH2)-containing phosphatase (SHP1), cytokine-inducible (CIS) SH2-containing protein, suppressor of cytokine signaling-1 (SOCS1) and protein inhibitor of activated signal transducer and activator of transcription 3 (STAT3) (PIAS3) in six HTLV-1 negative and seven HTLV-1 positive T-cell leukemia lines. The activation status of the JAK/STAT pathway was also examined. SHP1 mRNA and protein expression levels were selectively down regulated in all HTLV-1-infected transformed cell lines, while CIS, SOCS1, and PIAS3 protein expression were markedly but variably upregulated and the cells showed evidence of constitutive STAT3 activation. In acutely HTLV-1 infected primary CD4+ T-cells there was a gradual loss of SHP1 expression over 10 weeks in culture which correlated with progression from immortalization to transformation and loss of IL-2 dependence for growth. Two transformed cell lines that were established following HTLV-1 infection showed loss of SHP1 expression and overexpression of CIS, SOCS1, PIAS3. However, this overexpression was not adequate to block constitutive activation of the JAK/STAT pathway. Thus, multiple levels of IL-2 receptor signal deregulation are found in HTLV-1 transformed cells, which may be a result of early loss of SHP1 expression.

Adult↗

PubMed1997

Neuramide inhibits Epstein-Barr virus-induced transformation activity and proliferation of transformed B lymphocytes.

Neuramide, in Italy, is a prescription drug and contains various polypeptides, with molecular weights ranging between 10,000 and 1,000. It is commonly used in Italy for the clinical therapy of varicella-zoster and other viral herpetic diseases. In the present study, we investigated its effect on the in vitro transformation activity and transformed status of the Epstein-Barr virus (EBV), ab herpesvirus closely associated with infectious mononucleosis (IM), nasopharyngeal carcinoma (NPC) and Burkitt's lymphoma (BL). Antiviral effects of neuramide were evaluated on viral-induced immortalization, transformed status and DNA synthesis. Our results show that simultaneous and/or post-treatment of EBV-infected lymphocytes with neuramide, at a concentration of 2 inhibiting units (IU)/ml, blocks EBV-mediated transformation and related events, whereas pretreatment does not show any inhibiting activity against EBV. Neuramide was also found to be a potent inhibitor of the proliferation of EBV-transformed B lymphocytes in vitro. These results suggest that the molecular mechanisms of action of the drug should be investigated more closely and also support the necessity to further purify the active polypeptides, in order to improve its possible in vivo efficacy in EBV-associated diseases, such as infectious mononucleosis and other lymphoproliferative diseases.

Antimicrobial Cationic Peptides↗

PubMed1979

Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse.

Antisera prepared against BALB/c Meth A sarcoma in syngeneic or compatible F1 mice recognize a protein with an apparent molecular weight of 53,000 in extracts of [35S]methionine-labeled transformed BALB/c cells. This component, designated p53, was not detected in normal adult mouse fibroblasts, lymphoid cells, or hematopoietic cells or in mouse embryo cells or 3T3 cells. An extensive variety of antisera, including alloantisera and heterologous antisera directed against structural antigens of murine leukemia viruses, was tested for reactivity with p53; other than Meth A antisera, only comparably prepared antisera against another BALB/c sarcoma, CMS4, had anti-p53 activity. All transformed mouse cells tested were found to express p53; these tests included chemically induced sarcomas, leukemias, spontaneously transformed fibroblasts, and cells transformed by simian virus 40 and murine sarcoma virus. The presence of p53 in tumors of no known viral etiology indicates coding by resident cellular genes; this does not exclude endogenous viruses as the source of coding sequences or the possibility that transforming viruses code directly for p53.

Animals↗

PubMed1990

Retroviral expression of transforming growth factor-alpha does not transform fibroblasts or keratinocytes.

Transforming growth factor alpha (TGF alpha) is a peptide so named because it helps to impart anchorage-independent growth to normal rat kidney (NRK) cells in vitro and is secreted by many rodent and human tumor cells. To directly investigate the transforming properties of this factor, we constructed a replication-defective murine retrovirus that expresses the human sequence coding for TGF alpha. Infection of NIH/3T3 cells with the TGF alpha retrovirus led to the integration of a transcriptionally active provirus and overexpression of biologically active TGF alpha, but failed to induce morphologic transformation. Similarly, the TGF alpha retrovirus failed to induce morphologic transformation of five other types of rodent fibroblasts. We also investigated the effect of TGF alpha expression on the growth of BALB/MK mouse keratinocytes, which require epidermal growth factor (EGF) for proliferation. We show that exogenously added TGF alpha is an extremely potent mitogen for BALB/MK cells. However, retroviral expression of TGF alpha in BALB/MK cells failed to relieve dependence on exogenously added EGF (or TGF alpha) for cell growth. These results suggest that overexpression of TGF alpha does not, by itself, transform rodent fibroblasts or keratinocytes.

Animals↗

PubMed1992

Phenotypic transformation of normal rat kidney cells by transforming growth factor beta is not paralleled by enhanced production of a platelet-derived growth factor.

Phenotypic transformation of normal rat kidney (NRK) cells requires the concerted action of multiple polypeptide growth factors. Serum-deprived NRK cells cultured in the presence of epidermal growth factor (EGF) become density-inhibited at confluence, but they can be restimulated by a number of defined polypeptide growth factors, resulting in phenotypic cellular transformation. Kinetic data show that restimulation by transforming growth factor beta (TGF-beta) and retinoic acid is delayed when compared to induction by platelet-derived growth factor (PDGF), indicating that both TGF beta and retinoic acid may exert their growth-stimulating action by an indirect mechanism. Northern blot analysis shows that NRK cells express the genes for various polypeptide growth factors, including TGF beta 1, PDGF A-chain and basic fibroblast growth factor, but that the levels of expression are not affected by TGF beta or retinoic acid treatment. NRK cells also secrete low amounts of a PDGF-like growth factor into their extracellular medium, but the levels of secretion are insufficient to induce mitogenic stimulation and are unaffected by agents inducing phenotypic transformation. In combination with studies on the effects of anti-PDGF antibodies, it is concluded that phenotypic transformation of NRK cells by TGF beta and retinoic acid is not the result of enhanced production of a PDGF-like growth factor.

Animals↗

PubMed1983

Reduced synthesis of pp60src and expression of the transformation-related phenotype in interferon-treated Rous sarcoma virus-transformed rat cells.

Treatment of Rous sarcoma virus-transformed rat cells with rat interferon-alpha (specific activity, 10(6) U/mg of protein) for 24 h caused a 50% reduction in intracellular pp60src-associated protein kinase activity. Staphylococcus aureus V8 protease digestion of pp60src, derived from 32P-labeled monolayer cultures incubated with or without interferon, revealed no differences either in the phosphopeptide pattern or in the phosphoserine-phosphotyrosine ratio. However, [3H]leucine pulse-labeling experiments showed that the synthesis of pp60src was reduced by 42 to 48%, relative to the level of bulk protein synthesis, in the interferon-treated cultures. Rat interferon-alpha also reduced the growth rate of Rous sarcoma virus-transformed rat cells in a dose-dependent manner over a 72-h period. The decrease in growth rate was accompanied by increases in the thickness and number of actin fibers per cell and by a decline in intracellular tyrosine phosphorylation by pp60src. The results suggest that interferon can inhibit the expression of the transformation-related phenotype by selectively reducing the synthesis of the Rous sarcoma virus transforming gene product. However, the interferon effects on the cytoskeletal organization and proliferation of Rous sarcoma virus-transformed cells may be due at least in part to the predominance of interferon-induced phenotypic changes over those caused by pp60src.

Actins↗

PubMed1989

Resistance to oncogenic transformation in revertant R1 of human ras-transformed NIH 3T3 cells.

A flat revertant, R1, was isolated from human activated c-Ha-ras-1 (hu-ac-Ha-ras) gene-transformed NIH 3T3 cells (EJ-NIH 3T3) treated with mutagens. R1 contained unchanged transfected hu-ac-Ha-ras DNA and expressed high levels of hu-ac-Ha-ras-specific mRNA and p21 protein. Transfection experiments revealed that NIH 3T3 cells could be transformed by DNA from R1 cells but R1 cells could not be retransformed by Kirsten sarcoma virus, DNA from EJ-NIH 3T3 cells, hu-ac-Ha-ras, v-src, v-mos, simian virus 40 large T antigen, or polyomavirus middle T antigen. Somatic cell hybridization studies showed that R1 was not retransformed by fusion with NIH 3T3 cells and suppressed anchorage independence of EJ-NIH 3T3 and hu-ac-Ha-ras gene-transformed rat W31 cells in soft agar. These results suggest that the reversion and resistance to several oncogenes in R1 is due not to cellular defects in the production of the transformed phenotype but rather to enhancement of cellular mechanisms that suppress oncogenic transformation.

Animals↗

PubMedDate not supplied

Transforming growth factor beta 1 (TGF beta 1) down-regulates expression and function of proliferation-inducing molecules in HPV-transformed cells.

The epidemiologic association of human papillomavirus (HPV) infection with dysplasia and cervical cancer is well established. Transforming growth factor beta 1 (TGF beta 1) is a growth inhibitory protein for epithelial cells. To examine the phenotype of HPV-transformed cells, we examined expression of TGF beta 1 and a number of cellular proliferation-enhancing molecules which are known to be regulated by TGF beta 1, including bcl-2, c-jun and NFkB. Previous studies had identified significant induction of TGF beta 1 and concomitant down-regulation of other growth stimulatory molecules in experimental papillomas. We used HPV-16 and -18 transformed cell lines. The HPV-16 transformed cells showed down-regulation of bcl-2 and NFkB as well as NFkB function upon TGF beta 1 treatment. The results suggest that TGF beta 1 may exert antiproliferative effects on some HPV-transformed cells by down-regulating expression and function of different proliferation-enhancing molecules. It is uncertain if this function is virus type specific and/or related to state of tumor cell progression.

Base Sequence↗

PubMed1988

Transforming growth factor alpha in chemically transformed hamster oral keratinocytes.

The cheek pouch of the Syrian hamster is an excellent tissue for the experimental induction of oral cancer by carcinogenic chemicals. Lysate prepared from a cell line (HCPC-1) derived from one of these hamster oral tumors greatly increased the growth of these oral tumor cells in vitro. We now show that the mitogenic substance, transforming growth factor alpha (TGF-alpha), is present in all of the chemically transformed hamster oral tumors examined (in vitro and in vivo). In no adult normal tissue of the Syrian hamster can we detect expression of TGF-alpha. TGF-alpha could be partly or wholly responsible for the mitogenic activity detected in the lysate of the chemically transformed hamster oral keratinocytes. Both normal and chemically transformed hamster oral keratinocytes express the receptor to epidermal growth factor. The consistent detection of TGF-alpha and epidermal growth factor receptor mRNAs in these hamster oral tumor cells suggests that an autocrine growth mechanism might be operative. This hamster cheek pouch oral cancer model can be used for the molecular analysis of how TGF-alpha and epidermal growth factor receptor might be involved in the malignant transformation of epithelial tissues.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1989

Regulation of transforming growth factor alpha messenger RNA expression in a chemically transformed rat hepatic epithelial cell line by phorbol ester and hormones.

Transforming growth factor alpha (TGF-alpha) is produced by many transformed cells, but little is known about the regulation of its expression. We examined TGF-alpha mRNA levels in a set of cloned neoplastic cell lines derived by chemical transformation of a normal rat liver epithelial cell. The untransformed parental cell line, WB-344, did not express a detectable level of TGF-alpha mRNA, whereas GP6ac, a transformed line capable of autonomous growth in soft agar, expressed TGF-alpha. When GP6ac cells were treated with agents thought to regulate protein kinase C activity, e.g., the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), TGF-alpha mRNA levels increased by 8- to 11-fold. The induction of TGF-alpha mRNA was detectable at 2 h, was maximal at 8-12 h, and declined by 24 h. Angiotensin, bradykinin, epinephrine, and epidermal growth factor also increased TGF-alpha mRNA by 2- to 5-fold. In contrast, parental WB cells neither expressed TGF-alpha mRNA, nor responded to TPA. TPA also increased epidermal growth factor receptor mRNA in GP6ac cells but the effect was less prolonged; maximal levels were seen at 4 h after TPA exposure and returned to control levels by 12 h. TPA increased TGF-alpha mRNA in GP6ac cells, in part, by increasing transcription of the TGF-alpha gene as measured by run-on transcription rates in isolated nuclei. In addition, the induction of TGF-alpha by TPA was blocked by concurrent incubation with agents that inhibit protein synthesis. However, if TPA was present for at least 2 h, subsequent addition of cycloheximide enhanced the effect of TPA. This indicates that the induction of TGF-alpha in GP6ac cells is comprised of at least two phases demarcated by the requirement for protein synthesis. The time course of induction and the sensitivity to inhibition of protein synthesis distinguish the effect of TPA on TGF-alpha mRNA from that of other genes regulated by TPA, e.g., c-myc and c-fos. These data also suggest that chemical transformation of rat liver epithelial cells leads to expression of TGF-alpha mRNA, and that once expressed, TGF-alpha mRNA can be modulated in a protein kinase C-dependent manner.

Animals↗

PubMed1985

[Genetic transformation of somatic cells. VII. The loss of the transformant phenotype is accompanied by both stable and unstable changes in DNA].

From 6 clones of Chinese hamster cells varying in the rate of the loss of transformant phenotype and containing a thymidine kinase gene (tk-gene) of Herpes simplex virus type 1 (HSV1), 25 subclones negative in thymidine kinase (TK-) were isolated on a medium with 50 micrograms/ml 5-bromodeoxyuridine (BrdU). A study was made of the frequency of spontaneous reversions to the TK+ phenotype in cell populations of BrdU-resistant subclones, and of the transforming activity (upon transformation of TK- cells of A238 clone to the TK+ phenotype) of DNA preparations from a row BrdU-resistant subclones. In 7 of 11 BrdU-resistant subclones the TK- phenotype is associated with changes reducing significantly the transforming activity of DNA. Some of these alterations are stable and undergo no spontaneous reversion, while the other ones are unstable, being reversed or suppressed at a high frequency. BrdU-resistant subclones produced from clones more stable in transformant phenotype are on the whole more stable in the TK- phenotype than BrdU-resistant subclones from the clones with the high rate of the loss of the TK+ phenotype.

Animals↗

PubMed1988

Transforming growth factors produced by normal and neoplastically transformed rat liver epithelial cells in culture.

The secretion of transforming growth factors (TGFs) alpha and beta by normal, chemically transformed, and malignant rat liver epithelial cell lines was investigated. The WB-F344 normal cultured rat liver epithelial cell line does not secrete an epidermal growth factor-like (putatively TGF-alpha) activity, but several clonal cell strains derived from WB-F344 cells which had been treated with N-methyl-N'-nitro-N-nitrosoguanidine, especially those that expressed high levels of gamma-glutamyl transpeptidase, secreted TGF-alpha-like activity into their conditioned media. Cell lines obtained from tumors which were produced by these cell strains varied in their abilities to secrete TGF-alpha, even though they all expressed high levels of gamma-glutamyl transpeptidase activity. When two of the non-TGF-alpha-secreting tumor cell lines were transplanted into isogeneic rats, the tumors that formed contained high levels of TGF-alpha-like activity. Although epidermal growth-factor (hence, TGF-alpha also) inhibited the proliferation of several of these tumor cell lines in monolayer cultures, this growth factor often paradoxically stimulated the anchorage-independent growth of the same cell lines. In contrast to TGF-alpha-like activity, all cell lines/strains released TGF-beta activity into their conditioned media. However, while both normal or chemically transformed cell strains typically produced the inactive form of TGF-beta, the tumor cell lines tended to produce activated TGF-beta de novo. Anchorage-independent growth of cell lines that produced active TGF-beta was either stimulated, inhibited, or unaffected by TGF-beta. Cell lines that were inhibited by TGF-beta concurrently produced TGF-alpha which was usually able to overcome the negative "autocrine" effect of TGF-beta. We conclude that both TGF-alpha and TGF-beta, singly or in combination, are variously involved in the growth of transformed rat liver epithelial cells. TGF-alpha has a predominantly positive autocrine action on the growth of rat liver epithelial tumor cell lines. The "paracrine" effect of TGF-beta may be at least as important as its autocrine effect in the growth of these transformed epithelial cell lines.

Animals↗

PubMed1995

Transformation of chronic myelomonocytic leukemia to acute lymphoblastic leukemia: case report and review of the literature of lymphoblastic transformation of myelodysplastic syndrome.

If chronic myelomonocytic leukemia (CMML) transforms into an acute leukemic phase, the blast crisis is invariably myeloid. Occasionally, the other subtypes of myelodysplastic syndrome (MDS) (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation) have been noted to transform into acute lymphoblastic leukemia (ALL). We now report a case of CMML that transformed into ALL and we review the literature of 13 other cases of MDS with ALL transformation. Such cases provide suggestive clinical evidence that MDS can involve a pluripotent stem cell.

Cell Transformation, Neoplastic↗

PubMed1986

The phenotypic characteristics of simian sarcoma virus-transformed human fibroblasts suggest that the v-sis gene product acts solely as a PDGF receptor agonist in cell transformation.

Previous studies have indicated that the oncogene v-sis of simian sarcoma virus (SSV) encodes a growth factor that is structurally and functionally similar to platelet-derived growth factor (PDGF). In the present investigation we have analysed the phenotypic characteristics of human foreskin fibroblasts transformed by SSV. It was found that the PDGF receptors were extensively down-regulated. This finding is consistent with a high, local, extracellular concentration of a PDGF-like factor, synthesized by the transformed cell. The receptors were up-regulated by suramin, a drug that is known to dissociate PDGF and the v-sis product from the PDGF receptors. A cell-associated v-sis product of mol. wt 24,000 was identified by immunoprecipitation with PDGF antibodies; release of this component was induced by a high concentration of exogenous PDGF, indicating that a fraction of the product is associated with the PDGF receptors. SSV was not found to be an immortalizing virus; when serially passaged, SSV-transformed cells had essentially the same life-span as their non-transformed counterparts. Moreover, SSV did not induce growth in soft agar beyond the level afforded by exogenously added PDGF. Thus, the present study favors the notion that SSV transformation is mediated by a growth factor that mimics PDGF but has no further cellular effects.

Cell Division↗

PubMed1993

Hormone-conditional transformation by fusion proteins of c-Abl and its transforming variants.

Fusion of the hormone binding domain (HBD) of steroid receptors to transcription factors renders them hormone-dependent. We show here that an SH3-deleted, oncogenic variant of the Abl tyrosine kinase becomes hormone-dependent for transformation by fusion to the estrogen receptor (ER) HBD, extending the phenomenon to tyrosine kinases. Surprisingly, fusion of the HBD to the normal, non-transforming c-Abl (IV) protein activated transforming activity in a hormone-dependent fashion. In the presence of hormone, the c-Abl:ER fusion protein was transforming, cytoplasmic and tyrosine phosphorylated, whereas it was non-transforming, nuclear and hypophosphorylated without hormone. We have examined the kinetics of activation of the c-Abl:ER protein and found that protein synthesis is required both for kinase activation and for redistribution of the c-Abl:ER protein from the nucleus to the cytoplasm. We suggest that the activation of c-Abl could be due to HBD-mediated dimerization and/or to the ability to overexpress conditionally the normally toxic c-Abl protein. This novel approach may be applicable to a wide variety of proteins, particularly when activating mutations or physiological inducers are unknown or when the protein is toxic to cells.

3T3 Cells↗

PubMed1976

SV40 transformation of mouse brain cells: critical role of gene A in maintenance of the transformed phenotype.

Brain cells derived from the NIH Swiss mouse strain have been established in tissue culture. Astrocytic neuroglial cells, identified by morphology and staining properties, predominate. The brain cell culture was successfully transformed with SV40 wild type virus and with a representative early (A239) and late (C219) mutant. When subjected to growth analysis the A239 transformant displayed selective loss of six characteristics of the transformed phenotype at the restrictive temperature (40.5 degrees C): doubling time, saturation density, ability to grow in low serum, efficiency of growth on plastic and on normal brain cell layers, and cloning in soft agar. Temperature shift experiment demonstrated the reversibility of the differences in saturation density. T-antigen was expressed at both temperatures. Alteration in uptake of 2-deoxyglucose was not a characteristic of the transformed phenotype. The cell lines may be utility in brain culture work and in studies on the mechanism of SV40 transformation.

Antigens↗

PubMed1998

Malignant transformation of Syrian hamster embryo (SHE) cells in primary culture by malachite green: transformation is associated with abrogation of G2/M checkpoint control.

Malachite green (MG), consisting of green crystals with a metallic lustre, is highly soluble in water, cytotoxic to various mammalian cells and also acts as a liver tumour promoter. In view of its industrial importance and possible exposure to human beings, MG poses a potential environmental health hazard. We have earlier reported the malignant transformation of Syrian hamster embryo (SHE) cells by MG. In this study, we have studied the effects of MG on cell cycle phase distribution of normal and MG transformed Syrian hamster embryo cells in asynchronous and synchronous cell population. DNA flow cytometric analysis indicated that culturing cells for 48 h in medium containing MG at different concentrations induced dose-dependent G2/M arrest in normal cells. Malignantly transformed cells showed no such dose-responsive accumulation of cells at the G2/M phase of the cell cycle in response to MG. Synchronization studies indicated that in the control, both in the presence and absence of MG, cells followed a normal cell cycle pattern up to 16 h. After 16 h in the absence of MG, cells continued a normal cell cycle, whereas in the presence of MG they accumulated at G2/M phase of the cell cycle. This pattern of accumulation of cells at the G2/M checkpoint control was not observed in either untreated or MG-treated transformed cells. The present study indicates efficient operation of G2/M checkpoint control in control SHE cells and its abrogation in transformed SHE cells.

Animals↗