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At least 19 recordsLinked to original sources
PubMed1989

Growth modulatory effects of a liver-derived growth inhibitor, transforming growth factor beta 1, and recombinant tumor necrosis factor alpha, in normal and neoplastic cells.

The growth modulatory effects of a rat liver-derived growth inhibitor (LDGI), transforming growth factor beta 1 (TGF-beta 1), and recombinant tumor necrosis factor (rTNF-alpha) were examined in a variety of liver-derived and nonliver-derived normal and neoplastic cell culture systems. Normal rat liver epithelial (RLE) cells were highly sensitive to the growth inhibitory effects of LDGI (ID50 = 0.2 ng/ml) and TGF-beta 1 (ID50 = 0.25 ng/ml) but were less sensitive to rTNF-alpha (ID40 = 5000 Units/ml). Aflatoxin B1-transformed RLE cells showed sensitivity to the cytostatic effects of LDGI (ID50 = 1.5 ng/ml); however, these cells were completely resistant to the antiproliferative effects of TGF-beta 1 and rTNF-alpha. Clones isolated from these transformed cells, exhibited a wide range of sensitivities to LDGI but all of the clones were resistant to the growth inhibitory effects of both TGF-beta 1 and rTNF-alpha. Rat hepatoma Reuber cells were extremely sensitive to the antiproliferative effects of rTNF-alpha (ID50 = 10 Units/ml) but exhibited sensitivity to LDGI only at concentrations above 1.5 ng/ml and were resistant to the antiproliferative effects of TGF-beta 1. Rat hepatoma UVM 7777 cells and human hepatoma HepG2 cells, however, were insensitive to the growth inhibitory effects of all three factors. Among the nonliver-derived cells, human breast carcinoma (MCF-7) cells were extremely sensitive to rTNF-alpha (ID50 = 20 Units/ml, exhibited some sensitivity to LDGI (ID50 = 1 ng/ml), and were resistant to the antiproliferative effects of TGF-beta 1. In contrast, the rate of DNA synthesis is rat kidney fibroblasts and human foreskin fibroblasts was significantly stimulated in response to TGF-beta 1, LDGI, and rTNF-alpha. These data demonstrate that LDGI, TGF-beta 1, and rTNF-alpha exert positive and negative modulations of growth in different cell systems and that the growth regulatory effects of LDGI differ from those of TGF-beta 1 and rTNF-alpha in some cell types.

Animals↗
PubMed1995

A human keratinocyte cell line produces two autocrine growth inhibitors, transforming growth factor-beta and insulin-like growth factor binding protein-6, in a calcium- and cell density-dependent manner.

Two growth inhibitors were identified in culture medium conditioned by a human keratinocyte cell line, HaCat. TGF-beta was detected in media conditioned by growing or confluent HaCat cells, as well as in media conditioned at physiological (1 mM) or low (0.03 mM) Ca2+ concentrations. However, a considerable part of transforming growth factor beta (TGF-beta) in media conditioned at a physiological Ca2+ concentration was in active form, whereas most TGF-beta in media conditioned at a low Ca2+ concentration was latent. The other growth-inhibitory activity, which was detected only in media conditioned by confluent cells at a physiological Ca2+ concentration, was purified to homogeneity by a four-step procedure. The N-terminal amino acid sequence of the 33-kDa protein was identical with that of insulin-like growth factor binding protein-6 (IGFBP-6). Purified IGFBP-6 inhibited the growth of HaCat and Balb/MK keratinocyte cell lines, as well as Mv1Lu cells. The growth activity was also demonstrated by human recombinant IGFBP-6. In summary, HaCat cells secrete at least two possible autocrine growth inhibitors: TGF-beta which is secreted constitutively, but activated in a Ca(2+)-dependent manner, and IGFBP-6 which is secreted in a cell density- and Ca(2+)-dependent manner.

Amino Acid Sequence↗
PubMed1987

Antibodies against mammary derived growth inhibitor (MDGI) react with a fibroblast growth inhibitor and with heart fatty acid binding protein.

A polypeptide growth inhibitor, designated as mammary derived growth inhibitor, has previously been purified from lactating bovine mammary glands. Polyclonal rabbit antiserum raised against mammary derived growth inhibitor cross-reacts with bovine heart fatty acid binding protein and bovine peripheral myelin P2 protein. These results are consistent with the observation that the amino acid sequence of mammary derived growth inhibitor showed homology to the sequences of these proteins. In a parallel series of immunoblotting experiments, rabbit anti-mammary derived growth inhibitor also reacted specifically with a fibroblast growth inhibitor purified from the conditioned medium of cultured mouse 3T3 fibroblasts. These data suggest that bovine mammary derived growth inhibitor and mouse fibroblast growth inhibitor may share common structural features and raise the possibility that these growth inhibitors may together define a new family of growth regulatory molecules.

Animals↗
PubMed1983

Rapid selective effects by a growth inhibitor and epidermal growth factor on the incorporation of [35S]methionine into proteins secreted by African green monkey (BSC-1) cells.

Confluent African green monkey kidney (BSC-1) cells secrete a protein (Mr approximately equal to 24,000) that inhibits DNA synthesis and growth of the same cells. Using [35S]methionine to metabolically label proteins, we have found that this growth inhibitor selectively induces the BSC-1 cells to synthesize and secrete another protein with a relative Mr of 48,000 on NaDodSO4/polyacrylamide gels. We have called this protein "inhibitor-inducible protein" (IIP48). The maximal increase in rate of labeling of IIP48 due to treatment with the growth inhibitor averages 12-fold over the control. IIP48 is an N-glycosidically linked glycoprotein, and it is not a major intracellular protein. This protein is maximally induced within 4 to 6 hr of adding the growth inhibitor to the cells. This is an early response of these cells to the growth inhibitor and may represent a primary response to the growth inhibitor. Epidermal growth factor (EGF) increases the rate of labeling of three other secreted proteins (MrS 28,000, 59,000, and 61,000), which we have called "mitogen-inducible proteins" (MIP28, MIP59, and MIP61). The specific effects of both EGF and the growth inhibitor on the secreted levels of these proteins are inhibited if actinomycin D is added with the growth effectors. Thus, RNA synthesis appears necessary for the inductions. EGF and the growth inhibitor induce these secreted proteins by independent and noninteracting pathways.

Animals↗
PubMed2003

Bitter gourd proteinase inhibitors: potential growth inhibitors of Helicoverpa armigera and Spodoptera litura.

Proteinase inhibitors (PIs) from the seeds of bitter gourd (Momordica charantia L.) were identified as strong inhibitors of Helicoverpa armigera gut proteinases (HGP). Biochemical investigations showed that bitter gourd PIs (BGPIs) inhibited more than 80% HGP activity. Electrophoretic analysis revealed the presence of two major proteins (BGPI-1 and-2) and two minor proteins (BGPI-3 and-4) having inhibitory activity against both trypsin and HGP. The major isoforms BGPI-1 and BGPI-2 have molecular mass of 3.5 and 3.0 kDa, respectively. BGPIs inhibited HGP activity of larvae fed on different host plants, on artificial diet with or without added PIs and proteinases excreted in fecal matter. Degradation of BGPI-1 by HGP showed direct correlation with accumulation of BGPI-2-like peptide, which remained stable and active against high concentrations of HGP up to 3 h. Chemical inhibitors of serine proteinases offered partial protection to BGPI-1 from degradation by HGP, suggesting that trypsin and chymotrypsin like proteinases are involved in degradation of BGPI-1. In larval feeding studies, BGPIs were found to retard growth and development of two lepidopteran pests namely Helicoverpa armigera and Spodoptera litura. This is the first report showing that BGPIs mediated inhibition of insect gut proteinases directly affects fertility and fecundity of both H. armigera and S. litura. The results advocate use of BGPIs to introduce insect resistance in otherwise susceptible plants.

Animals↗
PubMed1997

Antitumor activity of the novel human breast cancer growth inhibitor, mammary-derived growth inhibitor-related gene, MRG.

A novel human tumor growth inhibitor was identified by differential cDNA sequencing. The predicted amino acid sequence of this tumor-suppressing factor has a significant sequence homology to mouse mammary-derived growth inhibitor and thus was named mammary-derived growth inhibitor-related gene (MRG). MRG was found to be expressed in normal and benign human breast tissues but not in breast carcinomas. In situ hybridization analysis demonstrated a stage-specific MRG expression as follows. MRG was barely detectable in breast carcinomas, showed partial and weak expression in benign hyperplasia, but was expressed at a high level in normal breast epithelial cells. To determine if MRG can modulate in vivo growth of human breast cancers, we transfected a full-length MRG cDNA into MDA-MB-231 human breast cancer cells and studied the orthotopic growth of MRG transfectants versus control transfectants in the mammary fat pad of athymic nude mice. Overexpression of MRG in human breast cancer cells significantly suppressed cell proliferation in vitro and tumor growth in an orthotopic nude mouse model. These results suggest that MRG has tumor-suppressing activity, and the loss of MRG expression may be involved in the development and progression of breast cancer.

Amino Acid Sequence↗
PubMed1987

Insulin-like synergistic stimulation of DNA synthesis in Swiss 3T3 cells by the BSC-1 cell-derived growth inhibitor related to transforming growth factor type beta.

A cell growth inhibitor (GI), purified from BSC-1 cell-conditioned medium, has little if any effect on DNA synthesis when added alone to monolayer cultures of quiescent Swiss mouse 3T3 cells in serum-free medium. However, the inhibitor, which is closely related to transforming growth factor type beta (TGF-beta), exhibits a pronounced synergistic stimulation of DNA synthesis in combination with certain peptide (bombesin, vasopressin) or polypeptide (platelet-derived growth factor) mitogens. A similar synergistic response has been demonstrated for TGF-beta purified from human platelets. In the presence of 3 nM bombesin, a half-maximal stimulation of DNA synthesis was obtained at a GI concentration of approximately 60 pg/ml, with a maximal response at approximately 600 pg/ml. The synergistic interactions demonstrated by GI or TGF-beta in stimulating Swiss 3T3 cells closely resemble those previously shown for insulin, and we have observed that GI does not synergize with insulin to stimulate DNA synthesis in these cells. Like insulin, and in contrast to bombesin, vasopressin, and platelet-derived growth factor, GI does not activate cellular inositolphospholipid hydrolysis, calcium mobilization, or cross-regulation of epidermal growth factor receptor affinity. These results raise the possibility that the biochemical pathways activated by GI/TGF-beta and insulin converge at a post-receptor stage.

Animals↗
PubMed1996

A growth inhibitor implicated in the growth arrest of human fibroblasts.

When quiescent human fibroblasts are induced to divide, the sugar composition of a growth inhibitory glycoprotein is modified. The kinetics of the incorporation of glucosamine in the growth inhibitor follows the kinetics of cell growth. It increases as cells approach quiescence and declines when cells initiate proliferation. The results suggest that the modification of the sugar composition of this glycoprotein is coupled with the variation of its inhibitory potential and this way to the initiation and the arrest of cell division.

Carbon Radioisotopes↗
PubMed1998

Suppression of mammary-derived growth inhibitor gene expression by growth hormone and insulin-like growth factor I.

When introduced into MCF-7 breast cancer cells, the mammary-derived growth inhibitor (MDGI) gene causes them to revert to a more normal behavior. MDGI is silenced in several human breast cancer cell lines and in most breast tumors. Antiestrogens (tamoxifen and ICI 182780), which are commonly used in breast cancer treatment, stabilize MDGI mRNA. Insulin-like growth factors (IGFs) are well characterized mitogenic and anti-apoptotic factors involved in mammary gland physiology. We demonstrate that MDGI gene expression was inversely correlated with IGF-II gene expression. In the mammary gland of growth hormone releasing hormone receptor mutant (Ghrhrlit/Ghrhrlit) mice, the MDGI gene was overexpressed. Administration of IGF-I or GH to Ghrhrlit/Ghrhrlit mice suppressed MDGI mRNA levels in a dose-dependent manner. Administration of the somatostatin analogue octreotide to pituitary intact rats in a manner previously shown to acutely suppress the GH/IGF-I axis, up-regulated mammary gland MDGI expression in a dose-dependent fashion. The data document a previously unrecognized role of IGF-I in the regulation of the tumor suppressor gene MDGI, in the mammary gland, and may aid in the design of new physiological approaches to breast cancer prevention and/or treatment.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Mouse parenchymal liver cells in culture secrete a growth inhibitor for myeloma cells.

METHODS: Growth inhibitory activity in the conditioned medium of mouse parenchymal liver cells was examined in three strains of myeloma cells. RESULTS: Two strains of myeloma cells were highly sensitive to a low concentration of mouse parenchymal liver cell derived growth inhibitor, whereas one strain was resistant to the same concentration. Interferon-alphabeta and transforming growth factor-beta activity were detected in mouse parenchymal liver cells, while interferon-gamma and tumor necrosis factor-alpha were not. The growth suppression exerted by mouse parenchymal liver cell derived growth inhibitor in the three myeloma strains was distinct from that exerted by transforming growth factor-beta, tumor necrosis factor-alpha, interferon-alphabeta and interferon-gamma. The mouse parenchymal liver cell derived growth inhibitor was eluted with a peak activity in the 18 kDa range and focused into pI values of 3.8-4.0, and it was lost when mouse parenchymal liver cells were treated with heat or trypsin. CONCLUSION: These results indicate that mouse parenchymal liver cell derived growth inhibitor differs from the well-characterized growth inhibitors, transforming growth factor-beta, tumor necrosis factor-alpha, interferon-alphabeta and interferon-gamma.

Animals↗
PubMed1991

IGFBP-1, an insulin like growth factor binding protein, is a cell growth inhibitor.

A novel cell growth inhibitor, IDF45 (inhibitory diffusible factor), was recently purified to apparent homogeneity. It is a bifunctional molecule: able to bind Insulin like growth factor (IGF) and to 100% inhibit DNA synthesis stimulated by serum in fibroblasts. It was of interest to verify whether other members of the IGF-binding protein (IGFBP) family show the same bifunctional growth inhibitory properties. In this paper we show that purified IGFBP-1 derived from amniotic fluid is a cell growth inhibitor. In chick embryo fibroblasts, it inhibited DNA synthesis stimulated by serum. However the stimulation was maximally 60% inhibited and half of the inhibition was observed with 100ng/ml IGFBP-1. So the specific activity of IGFBP-1 is lower than that of IDF45. IGFBP-1 also reversibly prevented the CEF growth. In the same cells IGFBP-1 inhibited DNA synthesis stimulated by IGF-I. We demonstrated that the same protein IGFBP-1 is able to inhibit DNA synthesis stimulated by serum and by IGF-I. The possibility that IGFBP-1 is a bifunctional molecule is discussed.

Amniotic Fluid↗
PubMed2001

Modulation of endothelial cell growth arrest and apoptosis by vascular endothelial growth inhibitor.

Vascular endothelial growth inhibitor (VEGI), a new member of the tumor necrosis factor family, is an endothelial cell-specific gene and a potent inhibitor of endothelial cell proliferation, angiogenesis, and tumor growth. We report here that VEGI mediates the following two activities in endothelial cells: early G(1) arrest in G(0)/G(1) cells responding to growth stimuli, and programmed death in proliferating cells. G(0)/G(1)-synchronized bovine aortic endothelial cells were treated with VEGI before and after the onset of the growth cycle. When the cells were stimulated with growth conditions but treated simultaneously with VEGI, a reversible, early-G(1) growth arrest occurred, evidenced by the lack of late G(1) markers such as hyperphosphorylation of the retinoblastoma gene product and upregulation of the c-myc gene. Additionally, VEGI treatment led to inhibition of the activities of cyclin-dependent kinases CDK2, CDK4, and CDK6. In contrast, VEGI treatment of cells that had entered the growth cycle resulted in apoptotic cell death, as evidenced by terminal deoxytransferase labeling of fragmented DNA, caspase 3 activation, and annexin V staining, all of which were lacking in nonproliferating cells treated with VEGI. Additionally, stress-signaling proteins p38 and JNK were not as fully activated by VEGI in quiescent as compared with proliferating populations. These findings suggest a dual role for VEGI, the maintenance of growth arrest and induction of apoptosis, in the modulation of the endothelial cell cycle.

Animals↗
PubMed1980

Purification of kidney epithelial cell growth inhibitors.

Two high molecular weight growth inhibitors have been isolated from the culture medium of BSC-1 cells, epithelial cells of African green monkey kidney. The purified kidney epithelial cell growth inhibitors, at ng/ml concentrations, reversibly arrest the growth of BSC-1 cells in the G1 phase of the cell cycle. Their action is selective; they are most active on BSC-1 cells, are less active as inhibitors of the growth of rat lung and human breast epithelial cells, and do not inhibit the growth of 3T3 mouse embryo fibroblasts ad human skin fibroblasts in culture. Their growth inhibitory action on BSC-1 cell cultures is counteracted by epidermal growth factor or calf serum.

Animals↗
PubMed1991

Elevated thymidine phosphorylase activity in psoriatic lesions accounts for the apparent presence of an epidermal "growth inhibitor," but is not in itself growth inhibitory.

An apparent tissue-specific growth inhibitor, or chalone, obtained from psoriatic lesions was tentatively identified in the 100-kDa fraction based upon inhibition of DNA synthesis, as measured by [3H]-thymidine uptake by a squamous cell carcinoma cell line, SCC 38. This fraction, however, failed to inhibit SCC 38 cell growth when assessed directly in a neutral red uptake assay. Characterization of the inhibitor of [3H]-thymidine uptake revealed it to have biochemical properties identical to thymidine phosphorylase: 1) molecular weight close to 100 kDa, 2) isoelectric point of 4.2, and 3) thymidine phosphorylase enzyme activity. Thus, we conclude that its ability to inhibit [3H]-thymidine uptake was due to thymidine catabolism rather than inhibition of DNA synthesis or growth inhibition. Examination of thymidine phosphorylase activity in keratome biopsies from psoriatic and normal skin demonstrated a twentyfold increase in activity in psoriatic lesions relative to non-lesional or normal skin. This increase in metabolism of thymidine was due to thymidine phosphorylase rather than uridine phosphorylase activity. The correlation between increased thymidine phosphorylase activity and increased keratinocyte proliferation in vitro (cultured) and in vivo (psoriasis), suggests that this enzyme may play a critical role in providing the thymidine necessary for keratinocyte proliferation.

Biopsy↗
PubMed1994

Inverse patterns of myelination and GAP-43 expression in the adult CNS: neurite growth inhibitors as regulators of neuronal plasticity?

In the central nervous system (CNS) myelin is present not only in white matter, but also in varying amounts in many gray matter areas. In addition to the function of electrical insulation of axons, myelin and oligodendrocytes contain molecules that are powerful inhibitors of neurite growth. Nevertheless plastic changes involving sprouting of nerve terminals occur in several brain regions of adult animals after partial lesions. In this study we have tried to correlate the plastic potential of CNS regions with the degree of their myelination. The expression of the growth-associated protein GAP-43 was used as an indicator of the potential for plastic changes, and a histological myelin stain was used to assess myelination. We have found that myelination and GAP-43 expression have strikingly inverse expression patterns in the majority of CNS gray matter areas. Densely myelinated regions, that is, most brainstem nuclei, the tegmentum, and the inferior colliculus, are low in GAP-43. In contrast, unmyelinated or lightly myelinated areas, such as the substantia gelatinosa of the spinal cord, the nucleus of the solitary tract, or the septum, express high levels of GAP-43. Areas known to show lesion-induced sprouting are typically high in GAP-43 and only lightly myelinated. During postnatal development the myelination pattern precedes the GAP-43 pattern, a sequence that is consistent with a role of myelin and the associated neurite growth inhibitors in modifying GAP-43 expression. Our results support the hypothesis that myelin-associated neurite growth inhibitors are involved in regulating the stability of neural connections.

Animals↗