Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q07644 (polypeptide)
 72,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has previously been shown that platelet-free human monocytes, when properly incubated in the presence of animal and human sera, became capable of producing large amounts of thromboxane A2 and prostaglandin E2. The characteristics of these processes are reported here. Prostaglandin biosynthesis was time and cell concentration dependent; 24 h of incubation at 37 degrees C and 0.5 X 10(6) cells per ml medium were found to give the most reproducible results. Human monocytes produced thromboxane A2 and prostaglandin E2 in a typical ratio which ranged from 2.0 to 5.0 (28 experiments). Animal and human sera were similarly effective, while serum obtained from platelet-free blood was much less active. The activity of all sera tested was stable to heating (100 degrees C for 2-10 min) and extreme pH values (pH 2 and 11). It was unstable when the serum was heated at pH 11 and after 2-mercaptoethanol treatment. These observations prompted us to check the effect of polypeptide growth factors having properties similar to those reported above, such as platelet-derived growth factor, fibroblast growth factor, epidermal growth factor as well as insulin and transferrin. None of these, alone or in various combinations, was capable of eliciting a stimulation comparable with that of serum. Stimulation due to sera was, as expected, dose dependently inhibited by acetylsalicylic acid and more efficiently by indomethacin; unexpectedly it was also inhibited by protein synthesis inhibitors such as actinomycin D and cycloheximide in conditions under which no toxic effect of the drugs was evident. On the basis of these results we conclude that: (a) polypeptide growth factor(s) with a molecular weight at least 30 000 (as judged by Amicon ultrafiltration) is involved in the regulation of prostaglandin biosynthesis); (b) such a factor(s) acts by inducing rather than by activating the cyclooxygenase system.
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PMID:Regulation of thromboxane A2 biosynthesis in platelet-free human monocytes and the possible role of polypeptide growth factor(s) in the induction of cyclooxygenase system. 308 20

The human tumor cell line HT-1080 was used as a model system to study the effects of transforming growth factor-beta (TGF beta) on polypeptide synthesis and proteolytic activity of malignant cells. Confluent cultures were exposed to TGF beta under serum-free conditions, and alterations in the production of proteins were examined by metabolic labeling and polypeptide analysis. TGF beta induced the synthesis and secretion of the Mr 47,000 endothelial type plasminogen activator inhibitor (PAI-1) as shown by reverse zymography, immunblotting, and immunoprecipitation analyses. TGF beta-induced PAI-1 was rapidly deposited in the growth substratum of the cells as shown by metabolic labeling and extraction of the cultures with sodium deoxycholate. Using pulse-chase experiments, we found a relatively fast turnover of substratum-associated PAI-1. Exogenously added urokinase released PAI-1 from the substratum even in the presence of the plasmin inhibitor aprotinin, suggesting a direct effect of urokinase. Immunoreactive complexes of higher molecular weight were subsequently detected in the medium. Epidermal growth factor, transforming growth factor-alpha, platelet-derived growth factor, and insulin did not elicit similar effects on the amount of PAI-1. TGF beta also inhibited the anchorage-independent growth of HT-1080 cells at the same concentrations at which it induced PAI-1. These results indicate that TGF beta can modulate the extracellular proteolytic activity of cultured cells by enhancing the secretion and deposition of PAI-1 into their microenvironment. It remains to be established whether TGF beta inhibition of anchorage-independent growth of these cells is associated with the induction of PAI-1.
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PMID:Transforming growth factor-beta induction of type-1 plasminogen activator inhibitor. Pericellular deposition and sensitivity to exogenous urokinase. 312 97

It has previously been shown that a heat- and acid-stable component of human and animal sera was capable of stimulating prostanoid biosynthesis in human blood monocytes, very probably by a mechanism involving cyclooxygenase induction. Many physico-chemical characteristics of this factor are similar to those of identified platelet factors. Here we show that human platelets are a rich source of this factor (serum monocytotropic factor) and that results from experiments using arachidonic acid or thrombin as releasers are consistent with its presence in platelet membranes. Serum monocytotropic factor has been purified 1500-fold by three chromatographic steps. Purification was more difficult when starting from platelet releasates or lysates. The purified serum monocytotropic factor had an apparent molecular mass of 70,000 as judged by Sephadex G-75 chromatography and by polyacrylamide gel electrophoresis; however, when subjected to HPLC on a gel permeation column in the presence of 6 M urea, one major peak corresponding to a relative molecular mass (Mr) of 30,000-35,000 was observed, which suggests a homodimeric structure. It is therefore very likely that human platelets store, in addition to the two well-identified polypeptide growth factors, platelet-derived growth factor and transforming growth factor-beta, a third polypeptide capable of regulating prostanoid production in monocytes.
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PMID:Purification and partial characterization of serum monocytotropic factor, a platelet-derived cyclooxygenase-inducing polypeptide. 312 80

An important event during wound healing is the contraction of newly formed connective tissue (granulation tissue) by fibroblasts. The role of polypeptide growth factors in the process of wound contraction was investigated by analyzing the influence of transforming growth factor beta (TGF-beta), platelet-derived growth factor on the ability of fibroblasts to contract a collagen matrix in an in vitro system. TGF-beta, but not the other growth factors tested, markedly enhanced the ability of BHK-21,3T3-L1, and human foreskin fibroblasts to contract collagen gels. These results suggest that TGF-beta released from platelets and inflammatory cells at sites of tissue injury stimulates fibroblasts to contract the provisional wound matrix and that this effect contributes to the ability of TGF-beta to accelerate wound healing.
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PMID:Transforming growth factor beta stimulates collagen-matrix contraction by fibroblasts: implications for wound healing. 316 78

The human teratocarcinoma stem cell line Tera-2 clone 13 is induced by retinoic acid to differentiate in vitro into endodermal or neuroectodermal cell types. In the absence of externally added growth factors, Tera-2 clone 13 cells proliferated at the same rate as in the presence of serum growth factors. Analysis of serum-free medium conditioned by Tera-2 clone 13 cells showed the presence of a polypeptide immunologically and biochemically related to platelet-derived growth factor (PDGF). In addition transforming growth factor beta (TGF-beta), but no TGF-alpha production could be detected. Tera-2 clone 13 cells specifically expressed high levels of the A-chain mRNA, but not the B-chain mRNA of PDGF. During retinoic acid induced differentiation the level of A-chain mRNA became markedly reduced. In contrast the TGF-beta mRNA levels increased significantly upon differentiation. The implications of these findings are discussed in terms of regulation of growth and differentiation in early embryos as well as in (human) teratocarcinomas.
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PMID:Differentially regulated production of platelet-derived growth factor and of transforming growth factor beta by a human teratocarcinoma cell line. 321 96

A serum-free assay has been established for studying the role of polypeptide growth factors in inducing loss of density-dependent inhibition of growth of normal rat kidney (NRK) cells. The process has been characterized by measuring the time course of [3H]thymidine incorporation into confluent, quiescent NRK cultures stimulated by defined polypeptide growth factors, in combination with cell counting studies, increases in DNA content, and cell cycle analysis by means of a fluorescence-activated cell sorter. It is shown that none of the growth factors tested (epidermal growth factor, platelet-derived growth factor, transforming growth factor-beta, and retinoic acid) is able to induce loss of density-dependent inhibition of growth by itself, but strong synergism was observed when combinations of growth factors were tested. None of the above factors was found to be essential, however, since any combination of three of the above four growth factors strongly induced the process. Strong parallels were observed between the growth factor requirements for inducing loss of density-dependent inhibition of growth under serum-free conditions and the requirements for induction of anchorage-independent proliferation under growth factor-defined assay conditions. This indicates that most likely the same cellular processes underlie these two aspects of phenotypic transformation, although data indicate that anchorage-independent proliferation may be a more restricted property of phenotypic transformation than loss of density dependence of proliferation. It is concluded that phenotypic transformation of NRK cells does not require specific polypeptide growth factors, but reflects the ability of these cells to respond to multiple growth factors.
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PMID:The role of polypeptide growth factors in phenotypic transformation of normal rat kidney cells. 327 52

The cooperative action of 17 beta-estradiol (E2) and polypeptide growth factors in stimulating proliferation of human breast cancer cells in vitro was investigated. To prevent background estrogenic stimulation, only phenol red-free media were used. When cultured in media supplemented with steroid-stripped serum in which all polypeptide growth factor activity had been chemically inactivated, MCF7 cells were unable to proliferate and became virtually quiescent. In the additional presence of insulin, epidermal growth factor (EGF), and E2, however, cells proliferated as rapidly as did cells cultured in media supplemented with fetal calf serum. Analysis by DNA flow cytometry showed that in the absence of external growth factors, MCF7 cells became arrested predominantly in the G1/G0 phase of the cell cycle. Upon addition of insulin in combination with EGF and E2, however, cells reentered the cell cycle with a high degree of synchrony. When added alone, E2 induced only slight mitogenic effects under these growth factor-defined conditions. In contrast, this steroid induced optimal proliferation in conventional steroid-stripped serum, which in itself contained considerable mitogenic activity. Insulin (at 10 micrograms/ml) was the most potent stimulator of MCF7 cell proliferation under growth factor-defined conditions, resulting in a more than sixfold increase in cell number after 96 hours. Other growth factors such as platelet-derived growth factor (PDGF), transforming growth factor beta (TGF beta), and EGF had little effect by themselves and only slightly influenced insulin-induced proliferation. At suboptimal concentrations of insulin (10-100 ng/ml), however, strong synergism was observed between E2 and insulin in inducing MCF7 proliferation. Using the CG5 cell line, a highly E2-sensitive MCF7 variant, synergism with E2 was already observed at 1 ng/ml insulin. It is concluded that MCF7 cells require insulin (or insulin-like growth factors) for proliferation. At suboptimal insulin concentrations, E2 acts synergistically with insulin, possibly by inducing autocrine production of polypeptide growth factors by these cells.
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PMID:Mitogenic stimulation of human breast cancer cells in a growth factor-defined medium: synergistic action of insulin and estrogen. 327 77

A completely serum-free assay method has been used to compare the mitogenic activities of polypeptide growth factors and estrogens with MCF-7 and T47D human breast cancer cells in culture. The lines were maintained in a viable, slowly dividing condition in Ham's F12 and Dulbecco's modified Eagle's medium (1:1) supplemented with sodium bicarbonate (2.2 g/liter), 15 mM 4-(2-hydroxyethyl)-1-piperazineethane-sulfonic acid, human transferrin (10 micrograms/ml), and bovine serum albumin (200 micrograms/ml) (designated Tf/BSA). This medium allowed the assay of mitogenic activities as measured by multiple rounds of cell division and permitted comparisons of the biological potencies of growth factors within functional families as well as of dissimilar mitogens. Insulin-like growth factor I (IGF-I) was the most potent mitogen studied, showing ED50 values of 160 pg/ml and 1.7 ng/ml with the MCF-7 and T47D cells, respectively. Insulin-like growth factor II and insulin were less active, with ED50 values of 0.55 and 1.2 ng/ml with MCF-7 cells and 4.3 and 10 ng/ml with the T47D cell line, respectively. Mitogens sharing epidermal growth factor-like functional properties had ED50 values from 35 pg/ml to 2.5 ng/ml, while transforming growth factor type beta and platelet-derived growth factor had no detectable stimulatory effects. Basic fibroblast growth factor had ED50 values of 0.42 ng/ml and 3.7 ng/ml for the MCF-7 and T47D cells, respectively, while acidic fibroblast growth factor was nearly inactive. In phenol red-free Tf/BSA, 17 beta-estradiol caused a 60% increase in MCF-7 cell numbers over controls in 8 days while having no effect on growth of the T47D cell line. From MCF-7 conditioned Tf/BSA medium, IGF-I was identified by biological activity, by radioimmunoassay (approximately equal to 2 pg/ml) and by estimation of molecular weight (8,000) under dissociating conditions. The concentration of IGF-I was not affected by 17 beta-estradiol treatment. The data indicate that induction of acid stable, low molecular weight autocrine growth factors involved more regulation than defined by estrogens alone. The minimal effects of 17 beta-estradiol in Tf/BSA opened several possibilities including the putative roles of other serum-borne hormones, growth factors and regulators in autocrine growth factor induction.
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PMID:Differential responsiveness of human breast cancer cell lines MCF-7 and T47D to growth factors and 17 beta-estradiol. 328 39

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.
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PMID: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. 329 69

Platelet-derived growth factor is expressed as dimers of two homologous polypeptide chains, termed A and B, encoded by different genes. A and B chain mRNA levels in microvascular endothelial cells are increased by phorbol ester, thrombin, and transforming growth factor-beta (TGF-beta) and are reduced by agents that elevate cyclic AMP. In this report, we investigated the effects of these regulatory agents on A and B chain transcription rates. By nuclear run-on analysis, TGF-beta stimulated transcription of both A and B chain genes. Thrombin and phorbol ester stimulated B chain transcription and had little or no detectable effect on A chain transcription. Pretreatment of cultures with 50 microM forskolin, a potent activator of adenylyl cyclase, completely blocked B chain transcription by thrombin and TGF-beta, but did not inhibit A chain transcription induced by TGF-beta. These results show that expression of platelet-derived growth factor mRNA involves both positive and negative transcriptional regulation and that there are differences in the transcriptional control of the A and B chain genes.
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PMID:Transcriptional regulation of the A and B chain genes of platelet-derived growth factor in microvascular endothelial cells. 337 37


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