Showing papers on "Growth factor receptor inhibitor published in 1981"

Epidermal growth factor receptors.

Abstract: EGF-Rs are cell membrane glycoproteins of wide distribution. They have not yet been fully characterized or purified but are probably molecules of 170-190,000 mol. wt. in most cells. The growth factor EGF binds and will saturate cell surface receptors with a KA of about 5 X 10(9) M-1 although a receptor class with an affinity in excess of 10(10) M-1 has been detected in some cells. The number of receptors on a cell does not determine the level of its response. Some cell types have receptors which bind EGF, but with no mitogenic response. The ways in which receptor affinity and/or number is modulated are described. This and other evidence is reviewed in a search for a suitable model of a mechanism of action on the cell, which best fits the current data. There is ample evidence that EGF binds to the receptor; that ligand-receptor complexes cluster or aggregate; and then are internalized and degraded, but evidence for a direct connection between internalization and the subsequent mitogenic response is lacking. Good correlations between internalization and mitogenic responses have been observed and developed into a theory of endocytic activation, but there is a body of evidence which cannot be accommodated by this theory. Instead, an alternative model is suggested.

Nerve growth factor-induced alteration in the response of PC12 pheochromocytoma cells to epidermal growth factor

Abstract: PC12 cells, which differentiate morphologically and biochemically into sympathetic neruonlike cells in response to nerve growth fact, also respond to epidermal growth factor. The response to epidermal growth factor is similar in certain respects to the response to nerve growth fact. Both peptides produce rapid increases in cellular adhesion and 2-deoxyglucose uptake and both induce ornithine decarboxylase. But nerve growth factor causes a decreased cell proliferation and a marked hypertrophy of the cells. In contrast, epidermal growth factor enhances cell proliferation and does not cause hypertrophy. Nerve growth factor induces the formation of neuritis; epidermal growth factor does not. When both factors are presented simultaneously, the cells form neurites. Furthermore, the biological response to epidermal growth fact, as exemplified by the induction of ornithine decarboxylase, is attenuated by prior treatment of the cells with nerve growth factor. PC12 cells have epidermal growth factor receptors. The binding of epidermal growth factor to these receptors is rapid and specific, and exhibits an equilibrium constant of 1.9 x 10(-9) M. Approximately 80,000 receptors are present per cell, and this number is independent of cell density. Treatment of the cells with nerve growth factor reduces the amount of epidermal growth factor binding by at least 80 percent. The decrease in receptor binding begins after approximately 12-18 h of nerve growth factor treatment and is complete within 3 d. Scratchard plots indicate that the number of binding sites decreases, not the affinity of the binding sites for epidermal growth factor.

Growth factors modulate gonadotropin receptor induction in granulosa cell cultures

Abstract: Epidermal growth factor and fibroblast growth factor inhibited follicle-stimulating hormone-dependent induction of luteinizing hormone receptor in cultured ovarian granulosa cells of the rat. In contrast, platelet-derived growth factor potentiated the induction of luteinizing hormone receptor by follicle-stimulating hormone. These results indicate that growth factors, well known for their effects on mitosis and DNA synthesis in cultured mammalian cells, are also able to modulate hormone-dependent differentiation in an endocrine target cell.

Inhibition of ovarian and testicular steroiodogenesis by epidermal growth factor

Abstract: Epidermal growth factor (EGF), but not fibroblast growth factor, inhibits the gonadotropin stimulation of estrogen and testosterone production by primary cultures of ovarian granulosa and testicular Leydig cells, respectively. EGF also inhibits gonadal steroidogenesis induced by cholera toxin and (Bu)2cAMP, and the inhibitory effect of EGF is not associated with cell proliferation. EGF may play an important endocrine role in the regulation of steroidogenic functions of gonadal cells.

Epidermal growth factor receptor number decreases during rat liver regeneration.

Abstract: The potential role of epidermal growth factor (EGF) in the regulation of rat liver regeneration was examined by assessing the binding of 125I-EGF to hepatic membranes isolated at various times after partial hepatectomy. The results demonstrated a fall in 125I-EGF binding detectable as early as 8 h after partial hepatectomy. The nadir in EGF binding, less than 40% of that observed in sham-operated control rats, was seen 36 and 48 h after partial hepatectomy. Scatchard analysis showed that the decrease in binding capacity was due to a fall in receptor number. The specificity of the observed loss of EGF receptors was substantiated in parallel studies of 125I-insulin and 125I-wheat germ lectin binding; the binding of these ligands did not decrease appreciably during liver regeneration. The data are consistent with the hypothesis that EGF or a similar substance is one component of the complex humoral signal that regulates liver regeneration.

Mesenchymal cells from the human embryonic palate are highly responsive to epidermal growth factor

Abstract: An established line of mesenchymal cells from the human embryonic palate is highly sensitive to the stimulatory effect of epidermal growth factor on growth, labeled thymidine incorporation, and ornithine decarboxylase activity. The results suggest that epidermal growth factor may play a key role in development of various human embryonic and fetal tissues.

Transforming growth factors (TGFs): Properties and possible mechanisms of action

Abstract: Transforming growth factors (TGFs) are growth-promoting polypeptides that cause phenotypic transformation and anchorage-independent growth of normal cells. They have been isolated from several human and animal carcinoma and sarcoma cells. One TGF is sarcoma growth factor (SGF) which is released by murine sarcoma virus-transformed cells. The TGFs interact with epidermal growth factor (EGF) cell membrane receptors. TGFs are not detectable in culture fluids from cells which contain high numbers of free EGF cell membrane receptors. SGF acts as a tumor promoter in cell culture systems and its effect on the transformed phenotype is blocked by retinoids (vitamin A and synthetic analogs). The production of TGFs by transformed cells and the responses of normal cells to the addition of TGFs to the culture medium raise the possibility that cells "autostimulate" their own growth by releasing factors that rebind at the cell surface. The term "autocrine secretion" has been proposed for this type of situation where a cell secretes a hormone-like substance for which it has external cell membrane receptors. The autocrine concept may provide a partial explanation for some aspects of tumor cell progression.

Receptors for insulinlike growth factor I are defective in fibroblasts cultured from a patient with leprechaunism.

Abstract: We previously have demonstrated that fibroblasts from a patient with leprechaunism exhibited markedly decreased insulin binding to insulin receptors and that the ability of insulin to stimulate glucose incorporation in the patient's cells was greatly impaired In addition, the insulinlike growth factor, multiplication-stimulating activity (MSA), also exhibited an impaired ability to stimulate glucose incorporation in the patient's fibroblasts, although in normal fibroblasts this response appears to be mediated by an insulinlike growth factor receptor The present study examines 125I-labeled insulinlike growth factor I (IGF-I) binding to patient's and control fibroblasts 125I-labeled IGF-I binds to a specific IGF-I receptor in normal fibroblasts At steady state, binding was inhibited by unlabeled IGF-I, IGF-II, MSA III-2, MSA II, insulin, and proinsulin, in order of potency, but not by high concentrations of epidermal growth factor and human growth hormone, chemically unrelated polypeptides 125I-labeled IGF-I binding to patient's cells was decreased by approximately 75%, whereas binding of epidermal growth factor to its cell surface receptors was unaffected Computer curve-fitting of untransformed equilibrium binding data suggests that the decreased binding resulted from a decreased Ka for IGF-I The ability of the patient's IGF-I receptor to recognize insulin also appears to be altered Impaired IGF-I binding by the leprechaun patient's fibroblasts may contribute to the abnormal biological response to insulinlike growth factors observed in vitro and to the in utero growth retardation

Lysosomotropic amines inhibit mitogenesis induced by growth factors

Abstract: The stimulation of DNA synthesis by epidermal growth factor, insulin, and serum is inhibited by a variety of alkylamines when present for the duration of the stimulatory preincubation (20-24 hr). These results contradict an earlier report [Maxfield, F. R., Davies, P. J. A., Klempner, L., Willingham, M. C. & Pastan, I. (1979) Proc. Natl. Acad. Sci. USA 76, 5731-5735] and can be explained by differences in incubation conditions. The most straightforward interpretation of our results is that the mitogenic activities of growth factors are blocked by agents that inhibit the intracellular processing of hormone-receptor complexes. Therefore, the continued internalization and degradation of growth factors or their receptors within cells may play an important role in inducing mitogenesis in cultured human fibroblasts and may explain the prolonged requirement for epidermal growth factor in the culture medium (8 hr) to elicit a mitogenic response. We also found that bacitracin, a potent inhibitor of the enzyme transglutaminase, neither prevents receptor internalization or degradation in human fibroblasts nor inhibits the mitogenic activity of epidermal growth factor. These results suggest that transglutaminase activity may not be relevant to the mechanisms of growth-factor-induced receptor internalization or mitogenesis.

Action of retinoids and phorbol esters on cell growth and the binding of epidermal growth factor.

Abstract: Retinoids play, outside the visual process, a diverse and essential role in growth and development of vertebrates.',z Many of the biological effects have been identified by the study of nutritional deprivation in vivo as well as in vitro. These studies include the requirement of vitamin A for the male reproductive system; during vitamin A deficiency the germinal epithelium in the testis fails to produce sperm and the epididymal epithelium undergoes metaplasia to a keratinized state.3 The latter seems to be a more general response of epithelial cells to vitamin A deficiency, since uterine, vaginal, and respiratory epithelium4.5 and epidermis cells6 also undergo squamous metaplasia and eventually keratinization. Another activity of retinoids, which may be related, at least partially, to the maintenance of mucous secretion of epithelial cells, is their capability of delaying or preventing the development of certain epithelial carcinomas in vivo and in organ cultures.7-10 The anticarcinogenic activity of some retinoids has also been established by in vitro studies, which show an inhibition of chemical transformation by various retinoids.11-13 However, caution is warranted for considering retinoids solely as anticarcinogenic agents, since some reports have suggested a tumor-promoting effect in vivo. 14 Furthermore, retinoids can induce biochemical properties in cells that often accompany the transformed state.15.16

Somatomedin B: Mitogenic Activity Derived from Contaminant Epidermal Growth Factor

Abstract: The mitogenic effect of somatomedin B on human cultured glial cells was neutralized by the addition of antibodies to mouse epidermal growth factor. Somatomedin B contained epidermal growth factor--like activity, competing for binding to the epidermal growth factor receptor. It is concluded that contaminating epidermal growth factor may explain the entire mitogenic activity of somatomedin B.

Glucocorticoids inhibit the stimulatory effect of epidermal growth factor on the initiation of DNA synthesis.

Abstract: Confluent, quiescent Swiss 3T3 cells in culture can be stimulated to initiate DNA synthesis and divide by addition of growth factors to the culture medium Here we show that hydrocortisone and other steroids which have glucocorticoid activity inhibit the stimulation of these cells by epidermal growth factor (EGF) in contrast to their reported enhancement of stimulation by fibroblast growth factor (FGF) Binding studies using [3H]-triamcinolone acetonide show that Swiss 3T3 cells contain a single class of glucocorticoid receptor of uniform affinity (KD = 20 nM), and about 34,000 receptor sites per cell Those steroids which displace bound [3H]-triamcinolone acetonide are also effective in inhibiting the stimulation of DNA synthesis by EGF in the presence or absence of insulin, and the concentration of triamcinolone acetonide required for one-half maximal biological effect is in the same range as the KD A similar concentration is required for one-half maximal enhancement of the effect of FGF These results suggest that both the inhibitory and stimulatory effects of glucocorticoids may be mediated via these receptors, the different effects thus being due to differences in the intracellular events triggered by each growth factor

Epidermal growth factor: relationship between receptor down regulation in cultured NRK cells and epidermal growth factor enhancement of phosphorylation of a 170000 molecular weight membrane protein in vitro.

Abstract: Incubation of confluent nondividing NRK cells in serum-free media with unlabeled epidermal growth factor (EGF) leads to a reduction in the specific binding capacity for 125I-labeled EGF. This modulation of the binding capacity for 125I-labeled EGF by unlabeled EGF, termed receptor down regulation, was dependent on EGF concentration and time. Membranes from untreated NRK cells have a phosphorylating system which catalyzed in vitro the phosphorylation of numerous membrane components; this phosphorylating system was stimulated by EGF. Although EGF enhanced the phosphorylation of many membrane proteins, one major component with Mr 170K and a minor band of Mr 150K were primarily affected. A comparison of the membrane phosphoproteins of untreated and down-regulated cells by in vitro phosphorylation and NaDodSO4 gel electrophoresis revealed that down regulation of EGF receptors results in a specific decrease in 32P phosphorylation of the 170K- and 150K-dalton components to subsequent stimulation with EGF in vitro. We further characterized the modulation of phosphorylation of the 170K protein by down regulation with EGF and found it to be dependent on EGF concentration and time. These studies demonstrated a correlation between the loss of 125I-labeled EGF binding activity by the cells and the loss of the vitro EGF-dependent 32P phosphorylation of the 170K-dalton membrane protein. In addition, the results suggest that the major 170K Mr phosphoprotein band is a component of the receptor for EGF which is a substrate of the phosphorylation reaction.

Long-term epidermal growth factor-receptor internalization and processing in quiescent human fibroblasts.

Abstract: Epidermal growth factor is internalized into cells and concomitantly induces a massive clearance of up to 90% of its total surface receptors. The hormone-receptor complex is delivered to lysosomes and degraded or inactivated. Lysosomotropic alkylamines block the degradation but not the binding or internalization of ligand-receptor complexes and thus their presence results in a marked potentiation of intracellular accumulation of epidermal growth factor. We have used these alkylamines as pharmacological tools to trap internalized 125I-labeled epidermal growth factor and now report that the residual population of epidermal growth factor receptors remaining on human fibroblasts after completion of the receptor clearance process is not only accessible for ligand binding but also directs the continued internalization and degradation of this growth factor over prolonged periods of time. We also show that down regulation of epidermal growth factor receptors does not result in desensitization of cells to the mitogenic response.