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1
Massagué, J. "Transforming growth factor-beta modulates the high-affinity receptors for epidermal growth factor and transforming growth factor-alpha." Journal of Cell Biology 100, no. 5 (May 1, 1985): 1508–14. http://dx.doi.org/10.1083/jcb.100.5.1508.
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The epidermal growth factor (EGF) receptor mediates the induction of a transformed phenotype in normal rat kidney (NRK) cells by transforming growth factors (TGFs). The ability of EGF and its analogue TGF-alpha to induce the transformed phenotype in NRK cells is greatly potentiated by TGF-beta, a polypeptide that does not interact directly with binding sites for EGF or TGF-alpha. Our evidence indicates that TGF-beta purified from retrovirally transformed rat embryo cells and human platelets induces a rapid (t 1/2 = 0.3 h) decrease in the binding of EGF and TGF-alpha to high-affinity cell surface receptors in NRK cells. No change due to TGF-beta was observed in the binding of EGF or TGF-alpha to lower affinity sites also present in NRK cells. The effect of TGF-beta on EGF/TGF-alpha receptors was observed at concentrations (0.5-20 pM) similar to those at which TGF-beta is active in promoting proliferation of NRK cells in monolayer culture and semisolid medium. Affinity labeling of NRK cells and membranes by cross-linking with receptor-bound 125I-TGF-alpha and 125I-EGF indicated that both factors interact with a common 170-kD receptor structure. Treatment of cells with TGF-beta decreased the intensity of affinity-labeling of this receptor structure. These data suggest that the 170 kD high-affinity receptors for EGF and TGF-alpha in NRK cells are a target for rapid modulation by TGF-beta.
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Brown, P. I., R. Lam, J. Lakshmanan, and D. A. Fisher. "Transforming growth factor alpha in developing rats." American Journal of Physiology-Endocrinology and Metabolism 259, no. 2 (August 1, 1990): E256—E260. http://dx.doi.org/10.1152/ajpendo.1990.259.2.e256.
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Transforming growth factor-alpha (TGF-alpha) concentrations were measured in lung, brain, liver, and kidney of rats at three different ages (20 days gestation and 9 and 50 days postnatal). TGF-alpha concentrations were maximal in the lung and brain by 20 days of gestation and showed minimal changes during nursing (day 9) and young adulthood (day 50). The liver, which also showed maximal TGF-alpha concentration by 20 days of gestation, demonstrated a progressive reduction with age to nadir values in the young adult. In contrast to the pattern in other tissues, kidney had the lowest concentration of TGF-alpha in late gestation and showed an increase by 50 days of age. As TGF-alpha acts via the epidermal growth factor (EGF) receptor, its function in development may be analogous to that of EGF. Thus TGF-alpha may have a role in lung maturation and postinjury repair, liver repair and regeneration, and neuronal cell growth.
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Wong, D. T., P. F. Weller, S. J. Galli, A. Elovic, T. H. Rand, G. T. Gallagher, T. Chiang, M. Y. Chou, K. Matossian, and J. McBride. "Human eosinophils express transforming growth factor alpha." Journal of Experimental Medicine 172, no. 3 (September 1, 1990): 673–81. http://dx.doi.org/10.1084/jem.172.3.673.
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Transforming growth factor alpha (TGF-alpha) is a pleuripotential cytokine with diverse biological effects, including the ability to influence the proliferation of normal cells or neoplastic epithelial cells. Eosinophils are a subset of granulocytes that normally enter the peripheral tissues, particularly those beneath gastrointestinal, respiratory, and urogenital epithelium, where they reside in close proximity to the epithelial elements. In this study, we demonstrate that the great majority of eosinophils infiltrating the interstitial tissues adjacent to two colonic adenocarcinomas and two oral squamous cell carcinomas labeled specifically by in situ hybridization with a 35S-riboprobe for human TGF-alpha (hTGF-alpha). No other identifiable leukocytes in these lesions contained detectable hTGF-alpha mRNA. We also examined leukocytes purified from a patient with the idiopathic hypereosinophilic syndrome. 80% of these eosinophils, but none of the patient's neutrophils or mononuclear cells, were positive for hTGF-alpha mRNA by in situ hybridization, and 55% of these eosinophils were positive by immunohistochemistry with a monoclonal antibody directed against the COOH terminus of the mature hTGF-alpha peptide. Finally, the identification of the purified eosinophil-associated transcript as hTGF-alpha was confirmed by polymerase chain reaction product restriction enzyme analysis followed by Southern blot hybridization. In contrast to eosinophils from the patient with hypereosinophilic syndrome, the peripheral blood eosinophils from only two of seven normal donors had detectable TGF-alpha mRNA and none of these eosinophils contained immunohistochemically detectable TGF-alpha product. Taken together, these findings establish that human eosinophils can express TGF-alpha, but suggest that the expression of TGF-alpha by eosinophils may be under microenvironmental regulation. Demonstration of TGF-alpha production by tissue-infiltrating eosinophils and the eosinophils in the hypereosinophilic syndrome identifies a novel mechanism by which eosinophils might contribute to physiological, immunological, and pathological responses.
4
Lee, D. C., R. Rochford, G. J. Todaro, and L. P. Villarreal. "Developmental expression of rat transforming growth factor-alpha mRNA." Molecular and Cellular Biology 5, no. 12 (December 1985): 3644–46. http://dx.doi.org/10.1128/mcb.5.12.3644-3646.1985.
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Expression of the gene encoding transforming growth factor-alpha (TGF alpha) was examined in developing rat embryos by using a cloned TGF alpha cDNA as a hybridization probe. Northern blot analysis of RNA isolated from whole fetuses revealed that TGF alpha mRNA was present at relatively high levels in 8- through 10-day-old embryos and then declined to the low or undetectable level, which is characteristic of adult tissues before birth. The level of TGF alpha mRNA present during early gestation was similar to that present in retrovirus-transformed cells in culture, suggesting that TGF alpha expression is not highly localized in the embryo. These observations are consistent with the hypothesis that TGF alpha plays a role in development, possibly as a fetal growth factor.
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Lee, D. C., R. Rochford, G. J. Todaro, and L. P. Villarreal. "Developmental expression of rat transforming growth factor-alpha mRNA." Molecular and Cellular Biology 5, no. 12 (December 1985): 3644–46. http://dx.doi.org/10.1128/mcb.5.12.3644.
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Expression of the gene encoding transforming growth factor-alpha (TGF alpha) was examined in developing rat embryos by using a cloned TGF alpha cDNA as a hybridization probe. Northern blot analysis of RNA isolated from whole fetuses revealed that TGF alpha mRNA was present at relatively high levels in 8- through 10-day-old embryos and then declined to the low or undetectable level, which is characteristic of adult tissues before birth. The level of TGF alpha mRNA present during early gestation was similar to that present in retrovirus-transformed cells in culture, suggesting that TGF alpha expression is not highly localized in the embryo. These observations are consistent with the hypothesis that TGF alpha plays a role in development, possibly as a fetal growth factor.
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Chen, M. C., A. T. Lee, W. E. Karnes, D. Avedian, M. Martin, J. M. Sorvillo, and A. H. Soll. "Paracrine control of gastric epithelial cell growth in culture by transforming growth factor-alpha." American Journal of Physiology-Gastrointestinal and Liver Physiology 264, no. 2 (February 1, 1993): G390—G396. http://dx.doi.org/10.1152/ajpgi.1993.264.2.g390.
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Studying primary cultures of replicating canine oxyntic mucosal cells, we found evidence for modulation of cell growth by endogenous factors. [3H]thymidine incorporation into DNA was rapid with cells cultured in medium free of serum or added growth factors, and growth rates of these cultures were markedly dependent on plating density, indicating mitogenic control by soluble endogenous growth factors. Data indicated that endogenous transforming growth factor-alpha (TGF-alpha) exerted mitogenic control under the following conditions. 1) TGF-alpha was detected in the cultured cells by radioimmunoassay and immunohistochemistry. 2) TGF-alpha-like immunoreactivity and receptor reactivity were present in the medium in concentrations sufficient to exert mitogenic control. 3) Receptors for TGF-alpha and epidermal growth factor (EGF) were present in the cultures. 4) Immunoabsorption by a TGF-alpha-specific antisera reduced [3H]thymidine incorporation. TGF-alpha was localized to parietal cells by immunohistochemistry and cell separation. In contrast, combined [3H]thymidine autoradiography and immunohistochemistry with anti-TGF-alpha did not detect TGF-alpha in dividing cells. We conclude that parietal cell TGF-alpha exerts paracrine control of mucosal cell growth in vitro, and we speculate that this is an important paracrine mechanism in vivo.
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Ebner, R., and R. Derynck. "Epidermal growth factor and transforming growth factor-alpha: differential intracellular routing and processing of ligand-receptor complexes." Cell Regulation 2, no. 8 (August 1991): 599–612. http://dx.doi.org/10.1091/mbc.2.8.599.
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Two structurally related but different polypeptide growth factors, epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha), exert their activities after interaction with a common cell-surface EGF/TGF-alpha-receptor. Comparative studies of the effects of both ligands have established that TGF-alpha is more potent than EGF in a variety of biological systems. This observation is not explained by differences in affinities of the ligands for the receptor, because the affinity-constants of both factors are very similar. We have compared the intracellular processing of ligand-receptor complexes using either EGF or TGF-alpha in two different cell systems. We found that TGF-alpha dissociates from the EGF/TGF-alpha-receptor at much higher pH than EGF, which may reflect the substantial difference in the calculated isoelectric points. After internalization, the intracellular TGF-alpha is more rapidly cleared than EGF, and a substantial portion of the released TGF-alpha represents undegraded TGF-alpha in contrast to the mostly degraded EGF. In addition, TGF-alpha did not induce a complete down-regulation of cell surface receptors, as observed with EGF, which is at least in part responsible for a much sooner recovery of the ligand-binding ability after down-regulation, in the case of TGF-alpha. These differences in processing of the ligand-receptor complexes may explain why TGF-alpha exerts quantitatively higher activities than EGF.
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Han, V. K. M., A. J. D'Ercole, and D. C. Lee. "Expression of transforming growth factor alpha during development." Canadian Journal of Physiology and Pharmacology 66, no. 8 (August 1, 1988): 1113–21. http://dx.doi.org/10.1139/y88-183.
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Transforming growth factors (TGFs) are polypeptides that are produced by transformed and tumour cells, and that can confer phenotypic properties associated with transformation on normal cells in culture. One of these growth-regulating molecules, transforming growth factor alpha (TGF-α), is a 50 amino acid polypeptide that is related to epidermal growth factor (EGF) and binds to the EGF receptor. Previous studies have shown that TGF-α is expressed during rodent embryogenesis between 7 and 14 days gestation. To investigate the cellular sites of TGF-α mRNA expression during development, we have performed Northern analyses and in situ hybridization histochemistry on the conceptus and maternal tissues at various gestational ages. Contrary to previous reports, both Northern analyses and in situ hybridization histochemistry indicate that TGF-α mRNA is predominantly expressed in the maternal decidua and not in the embryo. Decidual expression is induced following implantation, peaks at day 8, and declines through day 15 when the decidua is being resorbed. In situ hybridization revealed that expression of TGF-α mRNA is highest in the region of decidua adjacent to the embryo and is low or nondetectable in the uterus, placenta, and embryo. In addition, we could not detect TGF-α mRNA expression in other maternal tissues, indicating that the induction of TGF-α transcripts in the decidua is tissue specific, and not a pleiotropic response to changes in hormonal milieu that occur during pregnancy. The developmentally regulated expression of TGF-α mRNA in the decidua, together with the presence of EGF receptors in this tissue, suggests that this peptide may stimulate mitosis and angiogenesis locally by an autocrine mechanism. Because EGF receptors are also present in the embryo and placenta, TGF-α may act on these tissues by a paracrine or endocrine mechanism.
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Quigley, R., and M. Baum. "Effects of epidermal growth factor and transforming growth factor-alpha on rabbit proximal tubule solute transport." American Journal of Physiology-Renal Physiology 266, no. 3 (March 1, 1994): F459—F465. http://dx.doi.org/10.1152/ajprenal.1994.266.3.f459.
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The present in vitro microperfusion study examined the direct effects of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) on rabbit proximal convoluted tubule (PCT) solute transport. Tubules were perfused with an ultrafiltrate-like solution and bathed in an ultrafiltrate-like solution containing albumin. Albumin binding studies showed that both growth factors were highly protein bound with a free fraction of EGF of 0.31 +/- 0.04% and TGF-alpha of 1.08 +/- 0.15%. EGF at concentrations from 3 x 10(-11) M to 3 x 10(-8) M stimulated phosphate transport (JPhos) in a dose-dependent fashion but did not affect volume absorption (Jv) or bicarbonate transport (JtCO2). At 3 x 10(-7) M, EGF stimulated PCT Jv and JtCO2 in addition to the stimulation in JPhos. TGF-alpha stimulated Jv, JtCO2, and JPhos, but its effects were seen at a concentration that was 100-fold lower than that where EGF affected PCT transport. At 3 x 10(-13) M, TGF-alpha stimulated JtCO2, and at 3 x 10(-12) M, TGF-alpha also stimulated Jv and JPhos. EGF receptor downregulation with 3 x 10(-8) M EGF was able to block the effect of 3 x 10(-10) M TGF-alpha on Jv and JtCO2. Neither luminal EGF nor TGF-alpha had an effect on PCT transport. PCT bicarbonate and mannitol permeabilities were also not affected by either growth factor. These results demonstrate that EGF and TGF-alpha have direct effects on PCT solute transport.
10
Ryan, R. M., M. M. Mineo-Kuhn, C. M. Kramer, and J. N. Finkelstein. "Growth factors alter neonatal type II alveolar epithelial cell proliferation." American Journal of Physiology-Lung Cellular and Molecular Physiology 266, no. 1 (January 1, 1994): L17—L22. http://dx.doi.org/10.1152/ajplung.1994.266.1.l17.
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The type II alveolar epithelial cell plays a critical role in the repair of lung injury by repopulating the entire damaged alveolar epithelium. We report our studies of the effects of known growth factors on the in vitro proliferation of isolated neonatal rabbit type II cells. Transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF) increased [3H]thymidine incorporation, cell number, and labeling index above control. Transforming growth factor-beta (TGF-beta) decreased [3H]thymidine incorporation, cell number, and labeling index compared with control. When added simultaneously, TGF-beta blocked the stimulatory effect of TGF-alpha or EGF. If TGF-alpha is added before TGF-beta, the ability of TGF-beta to block the mitogenic effect of TGF-alpha was diminished the later in time TGF-beta was added. If TGF-beta was added first, later addition of TGF-alpha had no effect. The current work demonstrates that specific growth factors, including some known to be produced by other lung cells, alter the proliferation in vitro of isolated neonatal rabbit type II alveolar epithelial cells.
11
Vaughan, T. J., P. S. James, J. C. Pascall, and K. D. Brown. "Molecular cloning and tissue distribution of pig transforming growth factor α." Biochemical Journal 296, no. 3 (December 15, 1993): 837–42. http://dx.doi.org/10.1042/bj2960837.
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Transforming growth factor alpha (TGF alpha) was originally identified as a product of tumour tissues and transformed cells in culture. Although it is now clear that expression of this factor is not restricted to neoplastic cells, there remains relatively little information about the sites of expression of TGF alpha in normal tissues. Therefore, an amplified DNA fragment encoding the pig TGF alpha precursor was cloned by reverse transcription-PCR (RT-PCR) using RNA isolated from normal skin tissue as the template. Nucleotide sequence analysis predicts a 160-residue transmembrane polypeptide that differs from the rat, mouse and human TGF alpha precursors at 14, 15 and six sites respectively. The distribution of TGF alpha mRNA in a wide variety of pig tissues was analysed by RT-PCR, using oligonucleotide primers based on the pig TGF alpha cDNA sequence. TGF alpha transcripts were detected in RNA isolated from 17 of the 22 tissues analysed, including four previously unreported sites. Using an antibody raised against a synthetic TGF alpha peptide, we have immunolocalized TGF alpha protein to cells within the red pulp of the spleen and to the distal convoluted tubules of the kidney.
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Egesten, A., J. Calafat, EF Knol, H. Janssen, and TM Walz. "Subcellular localization of transforming growth factor-alpha in human eosinophil granulocytes." Blood 87, no. 9 (May 1, 1996): 3910–18. http://dx.doi.org/10.1182/blood.v87.9.3910.bloodjournal8793910.
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Eosinophils are involved in the inflammatory response seen in allergy and helminthic infestations. Eosinophils synthesize transforming growth factor-alpha (TGF-alpha), which may play a role in the development of the characteristic fibrosis seen in longstanding high eosinophilia. Using immunoelectron microscopic techniques, eosinophils from peripheral blood of healthy individuals and from one patient with high eosinophilia showed presence TGF-alpha in matrix of the specific crystalloid-containing granules. In cryosections, TGF-alpha was also visualized in a vesicular compartment of the cytoplasm. In double- labeling experiments, the TGF-alpha of this latter compartment did not colocalize with CD63, a marker for lysosomes, nor with albumin of secretory vesicles. In extracts from eosinophils, obtained from healthy donors, immunoreactive TGF-alpha could be detected by enzyme-linked immunosorbent assay-technique. In addition, sera from two patients with high eosinophilia showed TGF-alpha concentrations of 1.5 ng/mL and 164 pg/mL, respectively, whereas TGF-alpha could not be detected in serum from healthy controls. In conclusion, TGF-alpha is present in the specific granules, and in an additional vesicular compartment of the cytoplasm of eosinophils.
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McCaffrey, T. A., D. J. Falcone, C. F. Brayton, L. A. Agarwal, F. G. Welt, and B. B. Weksler. "Transforming growth factor-beta activity is potentiated by heparin via dissociation of the transforming growth factor-beta/alpha 2-macroglobulin inactive complex." Journal of Cell Biology 109, no. 1 (July 1, 1989): 441–48. http://dx.doi.org/10.1083/jcb.109.1.441.
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The control of smooth muscle cell (SMC) proliferation is determined by the combined actions of mitogens, such as platelet-derived growth factor, and the opposing action of growth inhibitory agents, such as heparin and transforming growth factor-beta (TGF-beta). The present studies identify an interaction between heparin and TGF-beta in which heparin potentiates the biological action of TGF-beta. Using a neutralizing antibody to TGF-beta, we observed that the short term antiproliferative effect of heparin depended upon the presence of biologically active TGF-beta. This effect was observed in rat and bovine aortic SMC and in CCL64 cells, but not in human saphenous vein SMC. Binding studies demonstrated that the addition of heparin (100 micrograms/ml) to medium containing 10% plasma-derived serum resulted in a 45% increase in the specific binding of 125I-TGF-beta to cells. Likewise, heparin induced a twofold increase in the growth inhibitory action of TGF-beta at concentrations of TGF-beta near its apparent dissociation constant. Using 125I-labeled TGF-beta, we demonstrated that TGF-beta complexes with the plasma component alpha 2-macroglobulin, but not with fibronectin. Heparin increases the electrophoretic mobility of TGF-beta apparently by freeing TGF-beta from its complex with alpha 2-macroglobulin. Dextran sulfate, another highly charged antiproliferative molecule, but not chondroitin sulfate or dermatan sulfate, similarly modified TGF-beta's mobility. Relatively high, antiproliferative concentrations of heparin (1-100 micrograms/ml) were required to dissociate the TGF-beta/alpha 2-macroglobulin complex. Thus, it appears that the antiproliferative effect of heparin may be partially attributed to its ability to potentiate the biological activity of TGF-beta by dissociating it from alpha 2-macroglobulin, which normally renders it inactive. We suggest that heparin-like agents may be important regulators of TGF-beta's biological activity.
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Barnard, J. A., W. H. Polk, H. L. Moses, and R. J. Coffey. "Production of transforming growth factor-alpha by normal rat small intestine." American Journal of Physiology-Cell Physiology 261, no. 6 (December 1, 1991): C994—C1000. http://dx.doi.org/10.1152/ajpcell.1991.261.6.c994.
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Transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF) are similar in structure and biological activity. In the present study, the distributions of TGF-alpha mRNA, TGF-alpha immunoreactivity, and TGF-alpha-EGF receptor mRNA were examined in epithelial and nonepithelial compartments of the jejunum, and the effect of TGF-alpha on growth of a jejunal crypt cell line (IEC-6) was determined. Epithelial cells eluted from the rat jejunal cryptvillus axis expressed TGF-alpha mRNA at twofold higher levels in the villus tip than in the crypt and EGF receptor mRNA at sevenfold higher levels in the villus tip. Expression of these two mRNA transcripts in the subepithelium was low. Immunohistochemical staining showed TGF-alpha immunoreactivity predominantly in the epithelium and muscularis. Immunostaining of villus cells was uniform, whereas crypt cells did not stain. IEC-6 cells bound 125I-EGF to a single class of high-affinity (dissociation constant = 833 pM) receptors. EGF and TGF-alpha (10 ng/ml) only modestly stimulated IEC-6 cell growth in the presence of 5% serum but increased expression of the protooncogenes c-jun and c-myc threefold over control cells. These findings suggest that, among the potential physiological roles for TGF-alpha produced by the jejunal epithelium, promotion of cell migration and modulation of fluid and electrolyte transport may be as relatively important as stimulation of cell proliferation.
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Yamakage, A., K. Kikuchi, E. A. Smith, E. C. LeRoy, and M. Trojanowska. "Selective upregulation of platelet-derived growth factor alpha receptors by transforming growth factor beta in scleroderma fibroblasts." Journal of Experimental Medicine 175, no. 5 (May 1, 1992): 1227–34. http://dx.doi.org/10.1084/jem.175.5.1227.
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Transforming growth factor beta (TGF-beta), a multifunctional cytokine, is an indirect mitogen for human fibroblasts through platelet-derived growth factor (PDGF), particularly the A ligand-alpha receptor arm of that system. TGF-beta effects on PDGF alpha receptor expression were studied in vitro using ligand binding techniques in three human dermal fibroblast strains: newborn foreskin, adult skin, and scleroderma (systemic sclerosis, SSc). Each cell strain responded differently to TGF-beta. In newborn foreskin fibroblasts, PDGF alpha receptor number decreased in a dose-dependent manner after exposure to low concentrations of TGF-beta (0.1-1 ng/ml). Responses of normal skin fibroblasts were varied, and mean net receptor number was unchanged. Increases in PDGF alpha receptor number by TGF-beta occurred consistently with SSc fibroblasts and low concentrations of TGF-beta (0.1-1 ng/ml) were particularly stimulatory. Increased surface expression of alpha receptor subunit by TGF-beta in SSc fibroblasts correlated with increased new PDGF alpha receptor synthesis as demonstrated by radioimmunoprecipitation analysis of metabolically labeled cells and with increased steady-state levels of corresponding mRNAs. In normal adult skin fibroblasts, TGF-beta had no effect on either synthesis or mRNA expression of alpha receptor subunits. Proliferative responses to PDGF-AA after pretreatment with TGF-beta correlated positively with effects of TGF-beta on expression of alpha receptor subunit. Decreased mitogenic responses to PDGF-AA were observed in foreskin fibroblasts, small changes in responses in adult fibroblasts, and significant increases in SSc fibroblasts. Thus, costimulation with PDGF-AA and TGF-beta selectively enhanced proliferation of fibroblasts with the SSc phenotype. Immunohistochemical examination of SSc and control skin biopsies revealed the presence of PDGF-AA in SSc skin. Data obtained by ligand binding, immunoprecipitation, mRNA, and mitogenic techniques are consistent with the hypothesis that activation of the PDGF-AA ligand/alpha receptor pathway is a characteristic of the SSc fibroblast and may contribute to the expansion of fibroblasts in SSc.
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Ihn, H., K. Kikuchi, Y. Soma, S. Sato, M. Fujimoto, T. Tamaki, A. Igarashi, and K. Takehara. "The stimulatory effects of PDGF and TGF-beta 1 on dermal fibroblast attachment." Acta Dermato-Venereologica 75, no. 5 (September 1, 1995): 367–71. http://dx.doi.org/10.2340/0001555575367371.
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We investigated the effects of various growth factors (platelet-derived growth factor (PDGF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), transforming growth factor-alpha (TGF-alpha), transforming growth factor-beta 1 (TGF-beta 1), tumor necrosis factor-alpha (TNF-alpha), keratinocyte growth factor (KGF)) on fibroblast attachment to plastic plates. It is thought that cell attachment to plastic plates in vitro may represent the step between cell migration and proliferation in vivo during wound healing. Among the growth factors examined, only PDGF and TGF-beta 1 significantly increased fibroblast attachment to both uncoated and collagen-coated plates in a concentration-dependent manner. The addition of anti-PDGF antibody abolished the enhancing effect of PDGF but not that of TGF-beta 1, suggesting that the effect of TGF-beta 1 is not through the autocrine induction of PDGF-related activities secreted by the fibroblasts themselves. These data suggest that PDGF and TGF-beta 1 regulate fibroblast attachment to the suitable environment in the process of dermal wound healing in vivo.
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Rogers, S. A., G. Ryan, and M. R. Hammerman. "Metanephric transforming growth factor-alpha is required for renal organogenesis in vitro." American Journal of Physiology-Renal Physiology 262, no. 4 (April 1, 1992): F533—F539. http://dx.doi.org/10.1152/ajprenal.1992.262.4.f533.
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The role of transforming growth factor-alpha (TGF-alpha) in metanephric development was examined. Metanephroi were removed from 13-day-old rat embryos and grown in organ culture for up to 6 days using serum-free chemically defined media. During this time the metanephroi increased in size and morphological complexity. Messenger RNA for TGF-alpha was present in the renal anlage. Immunoreactive TGF-alpha was produced by metanephroi in vitro and released into culture media. TGF-alpha of metanephric origin coeluted with recombinant human 125I-TGF-alpha after high-performance liquid chromatography of media. In contrast, epidermal growth factor was not detectable. Levels of TGF-alpha were relatively constant during 4 days in culture and averaged approximately 10(-10) M. Growth of the metanephric anlage, arborization of the ureteric bud, and tubulogenesis within the metanephric blastema were inhibited by the addition of anti-TGF-alpha antibodies to organ cultures. These data demonstrate production of TGF-alpha by developing rat metanephroi in organ culture. The peptide is necessary for growth and development in vitro. Our findings suggest a necessary role for TGF-alpha of metanephric origin as a promoter of renal organogenesis in vivo.
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Chantry, D., M. Turner, E. Abney, and M. Feldmann. "Modulation of cytokine production by transforming growth factor-beta." Journal of Immunology 142, no. 12 (June 15, 1989): 4295–300. http://dx.doi.org/10.4049/jimmunol.142.12.4295.
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Abstract Transforming growth factor-beta 1 (TGF-beta 1) is one of a family of polypeptides involved in the regulation of cell growth and differentiation. The effects of human rTGF-beta 1 on the production of IL-1 and TNF by activated PBMC were studied. The addition of TGF-beta 1 alone caused an increase in the levels of mRNA for IL-1 alpha, IL-1 beta, and TGF-alpha. This was due to increased transcription rather than enhanced mRNA stability. The induced mRNA were of the appropriate size as assessed by Northern blotting. However, the mRNA did not appear to be translated into protein, inasmuch as the translation products of IL-1 beta and TNF-alpha were not detected by RIA or ELISA. Furthermore, in experiments utilizing a neutralizing antibody to TGF-beta 1, we were unable to unmask IL-1 biologic activities and unable to detect TNF biologic activity in the WEHI 164 cytotoxicity assay. TGF-beta inhibited in a dose-dependent manner the induction of IL-1 beta by LPS or TNF but not by PHA and PMA. Similarly, LPS induction of TNF-alpha was blocked by TGF-beta, whereas induction of PMA and PHA was completely resistant. TGF-beta 1 did not increase PGE2 secretion or cause elevated intracellular cAMP; thus, the inhibitory effects of TGF-beta 1 seem not to be mediated by PGE2 or cAMP, which have both been implicated in post-transcriptional control of cytokine gene expression. These findings suggest a dual role for TGF-beta 1 in the regulation of cytokine production at both transcriptional and translational levels.
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Debinski, W., C. B. Siegall, D. Fitzgerald, and I. Pastan. "Substitution of foreign protein sequences into a chimeric toxin composed of transforming growth factor alpha and Pseudomonas exotoxin." Molecular and Cellular Biology 11, no. 3 (March 1991): 1751–53. http://dx.doi.org/10.1128/mcb.11.3.1751-1753.1991.
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TGF alpha-PE40 is a chimeric toxin made by replacing domain Ia of Pseudomonas exotoxin (PE) with transforming growth factor alpha (TGF alpha). We have now replaced a portion of domain Ib of PE with different polypeptides or an extra domain III of PE in transforming growth factor alpha-PE40 and maintained cell killing. Thus, TGF alpha-PE40 can be used to transport foreign protein sequences into the cytosol of cells.
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Debinski, W., C. B. Siegall, D. Fitzgerald, and I. Pastan. "Substitution of foreign protein sequences into a chimeric toxin composed of transforming growth factor alpha and Pseudomonas exotoxin." Molecular and Cellular Biology 11, no. 3 (March 1991): 1751–53. http://dx.doi.org/10.1128/mcb.11.3.1751.
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TGF alpha-PE40 is a chimeric toxin made by replacing domain Ia of Pseudomonas exotoxin (PE) with transforming growth factor alpha (TGF alpha). We have now replaced a portion of domain Ib of PE with different polypeptides or an extra domain III of PE in transforming growth factor alpha-PE40 and maintained cell killing. Thus, TGF alpha-PE40 can be used to transport foreign protein sequences into the cytosol of cells.
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Yang, J., L. W. Tyler, R. B. Donoff, B. Song, A. J. Torio, G. T. Gallagher, T. Tsuji, et al. "Salivary EGF regulates eosinophil-derived TGF-alpha expression in hamster oral wounds." American Journal of Physiology-Gastrointestinal and Liver Physiology 270, no. 1 (January 1, 1996): G191—G202. http://dx.doi.org/10.1152/ajpgi.1996.270.1.g191.
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Using hamster as an oral wound healing model, we examined eosinophils and their expression of transforming growth factor-alpha (TGF-alpha) and transforming growth factor-beta 1 (TGF-beta 1). Oral wounds healed approximately two times faster than their cutaneous counterparts. Eosinophils infiltrated prominently into oral wounds; however, unlike the dual expression of TGF-alpha and TGF-beta 1 in skin wounds, oral wound-associated eosinophils expressed TGF-beta 1, but not TGF-alpha. Because saliva is present in oral environments and contains epidermal growth factor (EGF) and TGF-alpha, sialoadenectomy was performed in this model to determine whether the lack of TGF-alpha expression by eosinophils in oral wounds is due to the presence of salivary EGF and/or TGF-alpha. We found that eosinophils in sialoadenectomized hamsters did express TGF-alpha during oral wound healing but that such expression was suppressed when EGF was added to their drinking water. Taken together, our findings suggest that eosinophil-derived TGF-alpha and salivary TGF-alpha/ EGF may have complementary roles in contributing to TGF-alpha in oral wound healing.
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Murphy-Ullrich, J. E., S. Schultz-Cherry, and M. Höök. "Transforming growth factor-beta complexes with thrombospondin." Molecular Biology of the Cell 3, no. 2 (February 1992): 181–88. http://dx.doi.org/10.1091/mbc.3.2.181.
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Thrombospondin (TSP) was demonstrated to inhibit the growth of bovine aortic endothelial cells, an activity that was not neutralized by antibodies to TSP or by other agents that block TSP-cell interactions but that partially was reversed by a neutralizing antibody to transforming growth factor-beta (TGF-beta). Similar to TGF-beta, TSP supported the growth of NRK-49F colonies in soft agar in a dose-dependent manner, which required epidermal growth factor and was neutralized by anti-TGF-beta antibody. Chromatography of a TSP preparation did not separate the TGF-beta-like NRK colony-forming activity from high molecular weight protein. However, when chromatography was performed at pH 11, this activity was dissociated from TSP. These results suggest that at least some growth modulating activities of TSP are due to TGF-beta associated with TSP by strong non-covalent forces. Most of the active TGF-beta released from platelets after degranulation was associated with TSP, as demonstrated by anti-TSP immunoaffinity and gel permeation chromatography. 125I-TGF-beta binds to purified TSP in an interaction that is specific in the sense that bound TGF-beta could be displaced by TGF-depleted TSP but not significantly by native TSP, heparin, decorin, alpha 2-macroglobulin, fibronectin, or albumin. Hence, TGF-beta can bind to TSP, and the complex forms under physiological conditions. Furthermore, TSP-associated TGF-beta is biologically active, and the binding of TGF-beta to TSP may protect TGF-beta from extracellular inactivators.
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Folkesson, H. G., J. F. Pittet, G. Nitenberg, and M. A. Matthay. "Transforming growth factor-alpha increases alveolar liquid clearance in anesthetized ventilated rats." American Journal of Physiology-Lung Cellular and Molecular Physiology 271, no. 2 (August 1, 1996): L236—L244. http://dx.doi.org/10.1152/ajplung.1996.271.2.l236.
Full textAbstract:
The effect of transforming growth factor-alpha (TGF-alpha) on alveolar liquid clearance was examined in ventilated, anesthetized rats. An isosmolar Ringer lactate solution with 10, 50, or 200 ng/ml TGF-alpha and 125I-labeled albumin as the alveolar protein tracer was instilled into the right lower lung lobe; the rats were studied for 1 and 4 h. Compared with control rats, addition of 50 ng/ml TGF-alpha to the instilled fluid increased alveolar liquid clearance by 47% over 1 h and by 66% over 4 h (P < 0.05). This increase was similar to the 50% increase in alveolar liquid clearance over 1 h in rats instilled with a beta-adrenergic agonist, salmeterol (28). There was a dose-dependent effect of TGF-alpha (10, 50, 200 ng/ml) on alveolar liquid clearance. The combination of both TGF-alpha and salmeterol did not have an additive effect on alveolar liquid clearance. The TGF-alpha-stimulated increase in alveolar liquid clearance was inhibited by amiloride (10(-4) M), indicating that the increase in clearance depended on increased Na+ uptake across the alveolar epithelium. There was only a twofold increase in intracellular cAMP levels in isolated rat alveolar epithelial type II cells after stimulation with TGF-alpha. In contrast, beta-adrenergic agonist treatment increased intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels more than tenfold. Genistein (10(-6) M), a tyrosine protein kinase inhibitor, inhibited the TGF-alpha-stimulated increase in alveolar liquid clearance. In summary, TGF-alpha can stimulate in vivo alveolar liquid clearance at a rate similar to beta-adrenergic stimulation by increasing Na+ uptake by alveolar epithelial type II cells. However, the effect may be mediated by a non-cAMP dependent mechanism. Because genistein blocked the increase in alveolar fluid clearance, the signal transduction may involve genistein-dependent phosphorylation.
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Abdullah, N. A., B. A. Torres, M. Basu, and H. M. Johnson. "Differential effects of epidermal growth factor, transforming growth factor-alpha, and vaccinia virus growth factor in the positive regulation of IFN-gamma production." Journal of Immunology 143, no. 1 (July 1, 1989): 113–17. http://dx.doi.org/10.4049/jimmunol.143.1.113.
Full textAbstract:
Abstract We have recently shown that epidermal growth factor (EGF) is capable of positive regulation of IFN-gamma production, thus establishing a functional relationship between nonhemopoietic growth factors and the immune system. In order to study this relationship further, EGF and the EGF-related growth factors transforming growth factor-alpha (TGF-alpha) and vaccinia virus growth factor (VGF), which stimulate cellular proliferation via binding to the EGF receptor, were studied for their functional and physicochemical effects on IFN-gamma production. In contrast to the positive signal of purified murine EGF and recombinant human EGF (both at 1 nM), neither synthetic TGF alpha nor recombinant VGF were capable of restoring competence for IFN-gamma production by Th cell-depleted spleen cell cultures. TGF-alpha and VGF, in molar excess, also failed to block the helper signal of EGF for IFN-gamma production. Thus TGF-alpha and VGF failed to functionally compete for the EGF receptor in the murine spleen cell system. Both TGF-alpha and VGF stimulated murine 3T3 cell proliferation at concentrations similar to those of EGF, and thus their failure to provide help for IFN-gamma production was not due to a general lack of biologic activity. Binding studies with 125I-EGF suggest that the EGF receptor on murine lymphocytes is not constitutively expressed, but inducible by the T cell mitogen staphylococcal enterotoxin A. TGF-alpha did not compete with 125I-EGF for the induced receptor. The data suggest that lymphocytes express a novel inducible EGF receptor that differs from that expressed on cells such as 3T3 fibroblasts.
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Sandgren, E. P., N. C. Luetteke, T. H. Qiu, R. D. Palmiter, R. L. Brinster, and D. C. Lee. "Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver." Molecular and Cellular Biology 13, no. 1 (January 1993): 320–30. http://dx.doi.org/10.1128/mcb.13.1.320-330.1993.
Full textAbstract:
To characterize the effect(s) of transforming growth factor alpha (TGF alpha) during multistage carcinogenesis, we examined tumor development in pancreas and liver of transgenic mice that coexpressed TGF alpha with either viral (simian virus 40 T antigens [TAg]) or cellular (c-myc) oncogenes. In pancreas, TGF alpha itself was not oncogenic, but it nevertheless dramatically accelerated growth of tumors induced by either oncogene alone, thereby reducing the host life span up to 60%. Coexpression of TGF alpha and TAg produced an early synergistic growth response in the entire pancreas together with the more rapid appearance of preneoplastic foci. Coexpression of TGF alpha and c-myc also accelerated tumor growth in situ and produced transplantable acinar cell carcinomas whose rate of growth was TGF alpha dependent. In liver, expression of TGF alpha alone increased the incidence of hepatic cancer in aged mice. However, coexpression of TGF alpha with c-myc or TAg markedly reduced tumor latency and accelerated tumor growth. Significantly, expression of the TGF alpha and myc transgenes in hepatic tumors was induced up to 20-fold relative to expression in surrounding nonneoplastic liver, suggesting that high-level overexpression of these proteins acts as a major stimulus for tumor development. Finally, in both pancreas and liver, combined expression of TGF alpha and c-myc produced tumors with a more malignant (less differentiated) appearance than did expression of c-myc alone, consistent with an influence of TGF alpha upon the morphological character of c-myc-induced tumor progression. These findings demonstrate the importance of TGF alpha expression during multistage carcinogenesis in vivo and point to a major role for this growth factor as a potent stimulator of tumor growth.
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Sandgren, E. P., N. C. Luetteke, T. H. Qiu, R. D. Palmiter, R. L. Brinster, and D. C. Lee. "Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver." Molecular and Cellular Biology 13, no. 1 (January 1993): 320–30. http://dx.doi.org/10.1128/mcb.13.1.320.
Full textAbstract:
To characterize the effect(s) of transforming growth factor alpha (TGF alpha) during multistage carcinogenesis, we examined tumor development in pancreas and liver of transgenic mice that coexpressed TGF alpha with either viral (simian virus 40 T antigens [TAg]) or cellular (c-myc) oncogenes. In pancreas, TGF alpha itself was not oncogenic, but it nevertheless dramatically accelerated growth of tumors induced by either oncogene alone, thereby reducing the host life span up to 60%. Coexpression of TGF alpha and TAg produced an early synergistic growth response in the entire pancreas together with the more rapid appearance of preneoplastic foci. Coexpression of TGF alpha and c-myc also accelerated tumor growth in situ and produced transplantable acinar cell carcinomas whose rate of growth was TGF alpha dependent. In liver, expression of TGF alpha alone increased the incidence of hepatic cancer in aged mice. However, coexpression of TGF alpha with c-myc or TAg markedly reduced tumor latency and accelerated tumor growth. Significantly, expression of the TGF alpha and myc transgenes in hepatic tumors was induced up to 20-fold relative to expression in surrounding nonneoplastic liver, suggesting that high-level overexpression of these proteins acts as a major stimulus for tumor development. Finally, in both pancreas and liver, combined expression of TGF alpha and c-myc produced tumors with a more malignant (less differentiated) appearance than did expression of c-myc alone, consistent with an influence of TGF alpha upon the morphological character of c-myc-induced tumor progression. These findings demonstrate the importance of TGF alpha expression during multistage carcinogenesis in vivo and point to a major role for this growth factor as a potent stimulator of tumor growth.
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Espevik, T., I. S. Figari, M. R. Shalaby, G. A. Lackides, G. D. Lewis, H. M. Shepard, and M. A. Palladino. "Inhibition of cytokine production by cyclosporin A and transforming growth factor beta." Journal of Experimental Medicine 166, no. 2 (August 1, 1987): 571–76. http://dx.doi.org/10.1084/jem.166.2.571.
Full textAbstract:
We investigated the ability of cyclosporin A (CsA) and transforming growth factor beta (TGF-beta) to modulate the production of TNF-alpha and TNF-beta and IFN-gamma by unseparated, nonadherent, and adherent PBMC. Treatment of unseparated PBMC with CsA resulted in a significant dose-dependent inhibition of all three cytokines ranging from greater than 90% inhibition for IFN-gamma and TNF-beta, to approximately 70% for TNF-alpha. Pretreatment of unseparated or nonadherent PBMC with TGF-beta inhibited the production of IFN-gamma by 60-70%. However, the inhibition of TNF-alpha and TNF-beta production by these cells was only minimally affected, and at 0.1-1 ng/ml TGF-beta could enhance TNF-alpha production by unseparated PBMC. In contrast, pretreatment of adherent PBMC with TGF-beta inhibited the production of TNF-alpha by approximately 60%. TGF-beta also inhibited both TNF-alpha production and tumor cell cytotoxicity mediated by murine peritoneal-derived macrophages. These observations indicate that the biological effects of CsA and TGF-beta on immune functions are of a wider range than previously reported.
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Mueller, S. G., A. J. Paterson, and J. E. Kudlow. "Transforming growth factor alpha in arterioles: cell surface processing of its precursor by elastases." Molecular and Cellular Biology 10, no. 9 (September 1990): 4596–602. http://dx.doi.org/10.1128/mcb.10.9.4596-4602.1990.
Full textAbstract:
Analysis of the transforming growth factor alpha (TGF alpha) cDNA predicts that the mature TGF alpha polypeptide is cleaved from the extracellular domain of its precursor, which is an integral membrane protein. Furthermore, the cleavage sites for the release of this mitogen are compatible with the participation of an elastaselike protease. We have immunohistochemically localized TGF alpha to the vascular smooth muscle cells in the arterioles. To investigate whether polymorphonuclear (PMN) leukocytic elastase, a blood-borne protease, could process the cell surface TGF alpha, NR6 cells were transfected with the rat TGF alpha cDNA. The cDNA encoded the entire open reading frame, and its expression was under the control of the mouse metallothionein I promoter. A cloned transfectant, termed 1B2, synthesized the TGF alpha precursor in a zinc-inducible manner, and the precursor was localized to the cell surface. Western blot (immunoblot) analysis indicated that treatment of the zinc-induced 1B2 cells with either PMN leukocytic or pancreatic elastase resulted in the release of the mature TGF alpha polypeptide. The released TGF alpha was bioactive, as it was capable of both competing with epidermal growth factor for binding to its receptor and stimulating [3H]thymidine incorporation in the mitogenic assay. Formaldehyde fixation of the 1B2 cells eliminated basal release of TGF alpha but allowed normal processing by both PMN leukocytic and pancreatic elastase to occur. However, human cathepsin G, bovine pancreatic alpha 1-chymotrypsin, collagenase, trypsin, subtilisin, and plasmin failed to release any detectable fragments of the TGF alpha precursor from the fixed cells. The location of TGF alpha in the arterioles and ability of PMN leukocytic elastase to process the membrane-bound TGF alpha precursor suggests a novel role for this elastase at the wound site.
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Mueller, S. G., A. J. Paterson, and J. E. Kudlow. "Transforming growth factor alpha in arterioles: cell surface processing of its precursor by elastases." Molecular and Cellular Biology 10, no. 9 (September 1990): 4596–602. http://dx.doi.org/10.1128/mcb.10.9.4596.
Full textAbstract:
Analysis of the transforming growth factor alpha (TGF alpha) cDNA predicts that the mature TGF alpha polypeptide is cleaved from the extracellular domain of its precursor, which is an integral membrane protein. Furthermore, the cleavage sites for the release of this mitogen are compatible with the participation of an elastaselike protease. We have immunohistochemically localized TGF alpha to the vascular smooth muscle cells in the arterioles. To investigate whether polymorphonuclear (PMN) leukocytic elastase, a blood-borne protease, could process the cell surface TGF alpha, NR6 cells were transfected with the rat TGF alpha cDNA. The cDNA encoded the entire open reading frame, and its expression was under the control of the mouse metallothionein I promoter. A cloned transfectant, termed 1B2, synthesized the TGF alpha precursor in a zinc-inducible manner, and the precursor was localized to the cell surface. Western blot (immunoblot) analysis indicated that treatment of the zinc-induced 1B2 cells with either PMN leukocytic or pancreatic elastase resulted in the release of the mature TGF alpha polypeptide. The released TGF alpha was bioactive, as it was capable of both competing with epidermal growth factor for binding to its receptor and stimulating [3H]thymidine incorporation in the mitogenic assay. Formaldehyde fixation of the 1B2 cells eliminated basal release of TGF alpha but allowed normal processing by both PMN leukocytic and pancreatic elastase to occur. However, human cathepsin G, bovine pancreatic alpha 1-chymotrypsin, collagenase, trypsin, subtilisin, and plasmin failed to release any detectable fragments of the TGF alpha precursor from the fixed cells. The location of TGF alpha in the arterioles and ability of PMN leukocytic elastase to process the membrane-bound TGF alpha precursor suggests a novel role for this elastase at the wound site.
30
Miettinen, P. J., and K. Heikinheimo. "Transforming growth factor-alpha (TGF-alpha) and insulin gene expression in human fetal pancreas." Development 114, no. 4 (April 1, 1992): 833–40. http://dx.doi.org/10.1242/dev.114.4.833.
Full textAbstract:
Transforming growth factor-alpha (TGF-alpha) mRNA is expressed in several pancreatic cancer cell lines, but its expression during normal fetal pancreas development has not been studied. We investigated the expression of TGF-alpha, its receptor (EGF-R) and insulin mRNA and their corresponding peptides in human fetal pancreata (15–20 gestation weeks). Polymerase chain reaction (PCR) and RNAase protection analysis revealed that TGF-alpha and insulin mRNAs were detectable in pancreas during the developmental span studied. In northern blot analysis a single band of 4.8 kilobases (kb) corresponding to the TGF-alpha transcript and a 0.6 kb for the insulin mRNA were detected in the pancreas. Using in situ hybridization, TGF-alpha mRNA expression was seen in a low copy number in both the exo- and endocrine pancreas. By immunohistochemistry TGF-alpha-immunoreactive cells were detected in the ducts, acini and islets showing that the mRNA was translated into protein. By contrast, insulin transcripts were detected in a high copy number, restricted to the islets of Langerhans. However, monoclonal insulin antibody detected less insulin containing cells than could be expected from the mRNA pattern suggesting that fetal beta-cells rapidly secrete insulin instead of storing it in the secretory granules. Alternatively, the translation of insulin mRNA could be inefficient. By double labeling the pancreas sections with polyclonal TGF-alpha antiserum and monoclonal insulin antibody the TGF-alpha- and insulin-like immunoreactivity was localized to beta-cells. Furthermore, mRNA for the TGF-alpha receptor, EGF-R, together with EGF-R-immunoreactive cells were also present in pancreas.(ABSTRACT TRUNCATED AT 250 WORDS)
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Arribas, J., and J. Massagué. "Transforming growth factor-alpha and beta-amyloid precursor protein share a secretory mechanism." Journal of Cell Biology 128, no. 3 (February 1, 1995): 433–41. http://dx.doi.org/10.1083/jcb.128.3.433.
Full textAbstract:
Cleavage and release of membrane protein ectodomains, a regulated process that affects many cell surface proteins, remains largely uncharacterized. To investigate whether cell surface proteins are cleaved through a shared mechanism or through multiple independent mechanisms, we mutagenized Chinese hamster ovary (CHO) cells and selected clones that were unable to cleave membrane-anchored transforming growth factor alpha (TGF-alpha). The defect in TGF-alpha cleavage in these clones is most apparent upon cell treatment with the protein kinase C (PKC) activator PMA, which stimulates TGF-alpha cleavage in wild-type cells. The mutant clones do not have defects in TFG-alpha expression, transport to the cell surface or turnover. Concomitant with the loss of TGF-alpha cleavage, these clones have lost the ability to cleave many structurally unrelated membrane proteins in response to PMA. These proteins include beta-amyloid precursor protein (beta-APP), whose cleavage into a secreted form avoids conversion into the amyloidogenic peptide A beta, and a group of cell surface proteins whose release into the medium is stimulated by PMA in wild type CHO cells but not in mutants. The mutations prevent cleavage by PKC-dependent as well as PKC-independent mechanisms, and thus affect an essential component that functions downstream of these various signaling mechanisms. We propose that regulated cleavage and secretion of membrane protein ectodomains is mediated by a common system whose components respond to multiple activators and act on susceptible proteins of diverse structure and function.
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Lobb, DK, and JH Dorrington. "Transforming growth factor-alpha: identification in bovine corpus luteum by immunohistochemistry and northern blot analysis." Reproduction, Fertility and Development 5, no. 5 (1993): 523. http://dx.doi.org/10.1071/rd9930523.
Full textAbstract:
Transforming growth factor-alpha (TGF-alpha), a product of the thecal cells, has potent mitogenic and steroidogenic influences on cells within the ovarian follicle. Whether TGF-alpha continues to be produced in those follicles that go on to ovulate and form a corpus luteum is currently under investigation. In the present study, TGF-alpha was localized in the bovine corpus luteum by means of immunoperoxidase staining using a monoclonal antibody for TGF-alpha that does not cross-react with epidermal growth factor. In corpora lutea from the mid-luteal phase of the cycle TGF-alpha staining was found predominantly in the large luteal cells. Northern blot analysis using a human TGF-alpha cDNA probe hybridized to the 4.5-4.8 kb TGF-alpha transcript in RNA from the corpus luteum. These studies provide new evidence that TGF-alpha, a potent paracrine regulator within the ovarian follicle, continues to be expressed in the corpus luteum.
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Gottlieb, A. B., C. K. Chang, D. N. Posnett, B. Fanelli, and J. P. Tam. "Detection of transforming growth factor alpha in normal, malignant, and hyperproliferative human keratinocytes." Journal of Experimental Medicine 167, no. 2 (February 1, 1988): 670–75. http://dx.doi.org/10.1084/jem.167.2.670.
Full textAbstract:
Transforming growth factor alpha (TGF-alpha) is a 50-amino acid peptide, previously demonstrated only in transformed cell lines and human tumors, which is structurally homologous to epidermal growth factor (EGF). TGF-alpha expression in keratinocytes from normal individuals, patients with psoriasis, and patients with malignant skin diseases was investigated using an mAb raised against synthetic human TGF-alpha. mAb A1.5 reacted with TGF-alpha, but not EGF, in a sensitive ELISA. Keratinocytes in eight nodular basal cell carcinomas, one morpheic basal cell carcinoma, and one squamous cell carcinoma demonstrated intense membranous immunoperoxidase staining with mAb A1.5. Of even greater interest was the observation that the overlying normal epidermis, as well as the epidermis from five normal skin specimens, were stained by the mAb. Keratinocytes in plaques from 18 psoriasis patients were more intensely stained than those from normal skin. Cultured normal keratinocytes demonstrated membranous staining with mAb A1.5. Absorption of mAb A1.5 with synthetic human TGF-alpha completely removed the reactivity of mAb A1.5 with both basal cell tumors and normal epidermis. The demonstration of TGF-alpha in normal keratinocytes suggests that it plays a role in normal keratinocyte growth, wound healing, and in the pathogenesis of acanthosis.
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Nixon, A. J., L. Broad, D. P. Saywell, and A. J. Pearson. "Transforming growth factor-alpha immunoreactivity during induced hair follicle growth cycles in sheep and ferrets." Journal of Histochemistry & Cytochemistry 44, no. 4 (April 1996): 377–87. http://dx.doi.org/10.1177/44.4.8601697.
Full textAbstract:
Transforming growth factor-alpha (TGF-alpha) has been associated with cell proliferation of keratinocytes and implicated in hair growth. We therefore examined changes in the immunocytochemical localization of TGF-alpha and cell proliferation markers in the skin of two unrelated species in which hair cycles could be induced, to elucidate the role of this growth factor in the control of fiber growth. Skin was collected from melatonin-treated ferrets (Mustela putorius furo), untreated Romney sheep (Ovis aries), and New Zealand Wiltshire sheep in which interruption of wool growth had been photoperiodically induced. Immunostaining patterns were very similar in ferrets and sheep. TGF-alpha immunoreactivity was observed in epithelial tissues of the skin but was not co-localized with cell proliferation markers. In anagen follicles, specific staining was most intense in the innermost cells of the outer root sheath and cortical cells in the keratogenous zone but was absent from inner root sheath or dermal papilla. TGF-alpha immunostaining diminished during catagen, although faint staining was retained in all epithelial cells. In telogen and early proanagen follicles, staining remained faint or was restricted to cells on the margin of the brush end and follicle neck. Immunoreactivity in the outer root sheath was reestablished in late proanagen. Sebaceous glands and epidermis were stained intensely throughout the hair cycle. TGF-alpha-immunoreactive components of skin extracts, analyzed by Western blotting, showed mobility corresponding to approximately 32 KD, but not to the size of the fully cleaved peptide. These results are consistent with an epithelial autocrine or juxtacrine, but not a mitogenic, function of TGF-alpha.
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Edwards, G. M., D. DeFeo-Jones, J. Y. Tai, G. A. Vuocolo, D. R. Patrick, D. C. Heimbrook, and A. Oliff. "Epidermal growth factor receptor binding is affected by structural determinants in the toxin domain of transforming growth factor-alpha-Pseudomonas exotoxin fusion proteins." Molecular and Cellular Biology 9, no. 7 (July 1989): 2860–67. http://dx.doi.org/10.1128/mcb.9.7.2860-2867.1989.
Full textAbstract:
TGF-alpha-PE40 is a hybrid protein composed of transforming growth factor-alpha (TGF-alpha) fused to a 40,000-dalton segment of Pseudomonas exotoxin A (PE40). This hybrid protein possesses the receptor-binding activity of TGF-alpha and the cell-killing properties of PE40. These properties enable TGF-alpha-PE40 to bind to and kill tumor cells that possess epidermal growth factor (EGF) receptors. Unexpectedly, TGF-alpha-PE40 binds approximately 100-fold less effectively to EGF receptors than does native TGF-alpha (receptor-binding inhibition IC50 = 540 and 5.5 nM, respectively). To understand the factors governing receptor binding, deletions and site-specific substitutions were introduced into the PE40 domain of TGF-alpha-PE40. Removal of the N-terminal 59 or 130 amino acids from the PE40 domain of TGF-alpha-PE40 improved receptor binding (IC50 = 340 and 180 nM, respectively) but decreased cell-killing activity. Substitution of alanines for cysteines at positions 265 and 287 within the PE40 domain dramatically improved receptor binding (IC50 = 37 nM) but also decreased cell-killing activity. Similar substitutions of alanines for cysteines at positions 372 and 379 within the PE40 domain did not significantly affect receptor-binding or cell-killing activities. These studies indicate that the PE40 domain of TGF-alpha-PE40 interferes with EGF receptor binding. The cysteine residues at positions 265 and 287 of PE40 are responsible for a major part of this interference.
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Edwards, G. M., D. DeFeo-Jones, J. Y. Tai, G. A. Vuocolo, D. R. Patrick, D. C. Heimbrook, and A. Oliff. "Epidermal growth factor receptor binding is affected by structural determinants in the toxin domain of transforming growth factor-alpha-Pseudomonas exotoxin fusion proteins." Molecular and Cellular Biology 9, no. 7 (July 1989): 2860–67. http://dx.doi.org/10.1128/mcb.9.7.2860.
Full textAbstract:
TGF-alpha-PE40 is a hybrid protein composed of transforming growth factor-alpha (TGF-alpha) fused to a 40,000-dalton segment of Pseudomonas exotoxin A (PE40). This hybrid protein possesses the receptor-binding activity of TGF-alpha and the cell-killing properties of PE40. These properties enable TGF-alpha-PE40 to bind to and kill tumor cells that possess epidermal growth factor (EGF) receptors. Unexpectedly, TGF-alpha-PE40 binds approximately 100-fold less effectively to EGF receptors than does native TGF-alpha (receptor-binding inhibition IC50 = 540 and 5.5 nM, respectively). To understand the factors governing receptor binding, deletions and site-specific substitutions were introduced into the PE40 domain of TGF-alpha-PE40. Removal of the N-terminal 59 or 130 amino acids from the PE40 domain of TGF-alpha-PE40 improved receptor binding (IC50 = 340 and 180 nM, respectively) but decreased cell-killing activity. Substitution of alanines for cysteines at positions 265 and 287 within the PE40 domain dramatically improved receptor binding (IC50 = 37 nM) but also decreased cell-killing activity. Similar substitutions of alanines for cysteines at positions 372 and 379 within the PE40 domain did not significantly affect receptor-binding or cell-killing activities. These studies indicate that the PE40 domain of TGF-alpha-PE40 interferes with EGF receptor binding. The cysteine residues at positions 265 and 287 of PE40 are responsible for a major part of this interference.
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Defeo-Jones, D., J. Y. Tai, R. J. Wegrzyn, G. A. Vuocolo, A. E. Baker, L. S. Payne, V. M. Garsky, A. Oliff, and M. W. Riemen. "Structure-function analysis of synthetic and recombinant derivatives of transforming growth factor alpha." Molecular and Cellular Biology 8, no. 8 (August 1988): 2999–3007. http://dx.doi.org/10.1128/mcb.8.8.2999-3007.1988.
Full textAbstract:
Transforming growth factor alpha (TGF-alpha) is a 50-amino-acid peptide that stimulates cell proliferation via binding to cell surface receptors. To identify the structural features of TGF-alpha that govern receptor-ligand interactions, we prepared synthetic peptide fragments and recombinant mutant proteins of TGF-alpha. These TGF-alpha derivatives were tested in receptor binding and mitogenesis assays. Synthetic peptides representing the N terminus, the C terminus, or the individual disulfide constrained rings of TGF-alpha did not exhibit receptor-binding or mitogenic activity. Replacement of the cysteines with alanines at positions 8 and 21, 16 and 32, and 34 and 43 or at positions 8 and 21 and 34 and 43 yielded inactive mutant proteins. However, mutant proteins containing substitutions or deletions in the N-terminal region retained significant biologic activity. Conservative amino acid changes at residue 29 or 38 or both and a nonconservative amino acid change at residue 12 had little effect on binding or mitogenesis. However, nonconservative amino acid changes at residues 15, 38, and 47 produced dramatic decreases in receptor binding (23- to 71-fold) and mitogenic activity (38- to 125-fold). These studies indicate that at least three distinct regions of TGF-alpha contribute to biologic activity.
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Defeo-Jones, D., J. Y. Tai, R. J. Wegrzyn, G. A. Vuocolo, A. E. Baker, L. S. Payne, V. M. Garsky, A. Oliff, and M. W. Riemen. "Structure-function analysis of synthetic and recombinant derivatives of transforming growth factor alpha." Molecular and Cellular Biology 8, no. 8 (August 1988): 2999–3007. http://dx.doi.org/10.1128/mcb.8.8.2999.
Full textAbstract:
Transforming growth factor alpha (TGF-alpha) is a 50-amino-acid peptide that stimulates cell proliferation via binding to cell surface receptors. To identify the structural features of TGF-alpha that govern receptor-ligand interactions, we prepared synthetic peptide fragments and recombinant mutant proteins of TGF-alpha. These TGF-alpha derivatives were tested in receptor binding and mitogenesis assays. Synthetic peptides representing the N terminus, the C terminus, or the individual disulfide constrained rings of TGF-alpha did not exhibit receptor-binding or mitogenic activity. Replacement of the cysteines with alanines at positions 8 and 21, 16 and 32, and 34 and 43 or at positions 8 and 21 and 34 and 43 yielded inactive mutant proteins. However, mutant proteins containing substitutions or deletions in the N-terminal region retained significant biologic activity. Conservative amino acid changes at residue 29 or 38 or both and a nonconservative amino acid change at residue 12 had little effect on binding or mitogenesis. However, nonconservative amino acid changes at residues 15, 38, and 47 produced dramatic decreases in receptor binding (23- to 71-fold) and mitogenic activity (38- to 125-fold). These studies indicate that at least three distinct regions of TGF-alpha contribute to biologic activity.
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Feild, J. A., R. H. Reid, D. J. Rieman, T. P. Kline, G. Sathe, R. G. Greig, and M. A. Anzano. "Structure-function analysis of human transforming growth factor-α by site-directed mutagenesis." Biochemical Journal 283, no. 1 (April 1, 1992): 91–98. http://dx.doi.org/10.1042/bj2830091.
Full textAbstract:
Site-directed mutants of transforming growth factor-alpha (TGF-alpha) were expressed in an Escherichia coli outer membrane protein A (ompA) expression/secretion vector under the transcriptional control of the lambda PL promoter. TGF-alpha mutant proteins were isolated from cell pellets using alkaline extraction with 0.1 M-Tris (pH 10.5). The levels of protein expression of 23 TGF-alpha mutants were comparable with those of wild-type TGF-alpha, as determined by immunoblotting and radioimmunoassay. An analysis of biological activity using as assays radioreceptor binding competition and colony formation in soft agar showed that the following mutations destroy the activity of TGF-alpha: Gly-19 to Val, Val-33 to Pro and Gly-40 to Val. Mutations of Arg-42 to Lys, Leu-48 to Ala, Tyr-38 to Trp or Phe-17 to Tyr significantly decrease, but do not destroy, biological activity when compared with the wild-type. Mutations in 14 other residues did not significantly alter receptor binding or colony-forming activity. These studies suggest that two domains localized at the surface of TGF-alpha are important in receptor binding and colony-forming activity. Domain I involves amino acid residues which include Tyr-38 and Leu-48; domain II includes residues Phe-15, Phe-17 and Arg-42.
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Wilcox, J. N., and R. Derynck. "Developmental expression of transforming growth factors alpha and beta in mouse fetus." Molecular and Cellular Biology 8, no. 8 (August 1988): 3415–22. http://dx.doi.org/10.1128/mcb.8.8.3415-3422.1988.
Full textAbstract:
Expression of mRNA for transforming growth factor alpha (TGF-alpha) and TGF-beta 1 during the fetal development of mice was evaluated by in situ hybridization. TGF-alpha mRNA was detected in 9- and 10-day fetuses but was absent in older fetuses. TGF-alpha mRNA-containing cells were found in the placenta, otic vesicle, oral cavity, pharyngeal pouch, first and second branchial arches, and developing kidneys. mRNA for TGF-beta 1 was present in hematopoietic cells of blood islands and capillaries and in the liver as it began to bud off on day 10 and function as a hematopoietic organ.
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Wilcox, J. N., and R. Derynck. "Developmental expression of transforming growth factors alpha and beta in mouse fetus." Molecular and Cellular Biology 8, no. 8 (August 1988): 3415–22. http://dx.doi.org/10.1128/mcb.8.8.3415.
Full textAbstract:
Expression of mRNA for transforming growth factor alpha (TGF-alpha) and TGF-beta 1 during the fetal development of mice was evaluated by in situ hybridization. TGF-alpha mRNA was detected in 9- and 10-day fetuses but was absent in older fetuses. TGF-alpha mRNA-containing cells were found in the placenta, otic vesicle, oral cavity, pharyngeal pouch, first and second branchial arches, and developing kidneys. mRNA for TGF-beta 1 was present in hematopoietic cells of blood islands and capillaries and in the liver as it began to bud off on day 10 and function as a hematopoietic organ.
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Hoffman, R. "Carrageenans inhibit growth-factor binding." Biochemical Journal 289, no. 2 (January 15, 1993): 331–34. http://dx.doi.org/10.1042/bj2890331.
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Carrageenans, a family of polysulphated carbohydrates, inhibited binding of basic fibroblast growth factor (bFGF), transforming growth factor beta 1 (TGF beta 1) and platelet-derived growth factor (PDGF). iota-Carrageenan was the most potent bFGF antagonist (IC50 = 0.4 +/- 0.1 microgram/ml), kappa-carrageenan was the most potent PDGF antagonist (IC50 = 1.7 +/- 1.3 micrograms/ml) and lambda-carrageenan was the most potent TGF beta 1 antagonist (IC50 = 19 +/- 2 micrograms/ml). None of the carrageenans, at concentrations up to 200 micrograms/ml, inhibited binding of insulin-like growth factor 1 or transforming growth factor alpha. Carrageenans are selective growth-factor antagonists and have potential for the treatment of disorders associated with the over-production of certain growth factors.
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Gentry, L. E., D. R. Twardzik, G. J. Lim, J. E. Ranchalis, and D. C. Lee. "Expression and characterization of transforming growth factor alpha precursor protein in transfected mammalian cells." Molecular and Cellular Biology 7, no. 5 (May 1987): 1585–91. http://dx.doi.org/10.1128/mcb.7.5.1585-1591.1987.
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Analysis of a cDNA clone derived from retrovirus-transformed rat fibroblasts has recently suggested that the mature 50-amino-acid form of transforming growth factor alpha (TGF alpha) is derived from a 159-amino-acid transmembrane precursor by proteolytic cleavage. To understand the processing of the TGF alpha precursor molecule in more detail, we have expressed this protein in baby hamster kidney (BHK) fibroblasts under control of the metal-ion-inducible metallothionein promoter and characterized the expressed precursor with site-specific antipeptide antibodies. One of the BHK transfectants, termed 5:2, expressed the TGF alpha mRNA in a cadmium- and zinc-inducible manner. The TGF alpha precursor protein was detected by immunoprecipitation analysis of radiolabeled cell cultures. In the induced 5:2 cells, a polypeptide of Mr 13,000 to 17,000 was readily identified by peptide antisera made to three different regions of the TGF alpha precursor protein. No such protein species were observed in BHK cells treated with cadmium and zinc or in uninduced 5:2 cells. However, two cell lines known to produce TGF alpha naturally, Leydig testicular tumor cells and Snyder-Theilan feline sarcoma virus-transformed Fisher rat embryo fibroblasts, possessed detectable levels of immunologically related Mr 13,000 to 17,000 proteins. Cell fractionation studies indicate that the Mr 13,000 to 17,000 species expressed in induced 5:2 cells is membrane associated, consistent with predictions based on the cDNA sequence of the TGF alpha precursor. Media conditioned by induced 5:2 cells contained epidermal growth factor receptor-competing activity, which, upon size fractionation, was similar in size to the mature processed form of TGF alpha. These data show that these nontransformed BHK cells possess the ability to process the TGF alpha precursor molecule into its native form.
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Gentry, L. E., D. R. Twardzik, G. J. Lim, J. E. Ranchalis, and D. C. Lee. "Expression and characterization of transforming growth factor alpha precursor protein in transfected mammalian cells." Molecular and Cellular Biology 7, no. 5 (May 1987): 1585–91. http://dx.doi.org/10.1128/mcb.7.5.1585.
Full textAbstract:
Analysis of a cDNA clone derived from retrovirus-transformed rat fibroblasts has recently suggested that the mature 50-amino-acid form of transforming growth factor alpha (TGF alpha) is derived from a 159-amino-acid transmembrane precursor by proteolytic cleavage. To understand the processing of the TGF alpha precursor molecule in more detail, we have expressed this protein in baby hamster kidney (BHK) fibroblasts under control of the metal-ion-inducible metallothionein promoter and characterized the expressed precursor with site-specific antipeptide antibodies. One of the BHK transfectants, termed 5:2, expressed the TGF alpha mRNA in a cadmium- and zinc-inducible manner. The TGF alpha precursor protein was detected by immunoprecipitation analysis of radiolabeled cell cultures. In the induced 5:2 cells, a polypeptide of Mr 13,000 to 17,000 was readily identified by peptide antisera made to three different regions of the TGF alpha precursor protein. No such protein species were observed in BHK cells treated with cadmium and zinc or in uninduced 5:2 cells. However, two cell lines known to produce TGF alpha naturally, Leydig testicular tumor cells and Snyder-Theilan feline sarcoma virus-transformed Fisher rat embryo fibroblasts, possessed detectable levels of immunologically related Mr 13,000 to 17,000 proteins. Cell fractionation studies indicate that the Mr 13,000 to 17,000 species expressed in induced 5:2 cells is membrane associated, consistent with predictions based on the cDNA sequence of the TGF alpha precursor. Media conditioned by induced 5:2 cells contained epidermal growth factor receptor-competing activity, which, upon size fractionation, was similar in size to the mature processed form of TGF alpha. These data show that these nontransformed BHK cells possess the ability to process the TGF alpha precursor molecule into its native form.
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Appleton, Tom, Shirine Usmani, John Mort, and Frank Beier. "MOLECULAR CONTROL OF ARTICULAR CARTILAGE DEGENERATION BY TRANSFORMING GROWTH FACTOR ALPHA." Clinical & Investigative Medicine 31, no. 4 (August 1, 2008): 2. http://dx.doi.org/10.25011/cim.v31i4.4787.
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Background: Articular cartilage degeneration is a hallmark of osteoarthritis (OA). We previously identified increased expression of transforming growth factor alpha (TGF?) and chemokine (C-C motif) ligand 2 (CCL2) in articular cartilage from a rat modelof OA (1,2). We subsequently reported that TGF? signalling modified chondrocyte cytoskeletal organization, increased catabolic and decreased anabolic gene expression and suppressed Sox9. Due to other roles in chondrocytes, we hypothesized that the effects ofTGF? on chondrocytes are mediated by Rho/ROCK and MEK/ERK signaling pathways. Methods: Primary cultures of chondrocytes and articularosteochondral explants were treated with pharmacological inhibitors of MEK1/2(U0126), ROCK (Y27632), Rho (C3), p38 MAPK (SB202190) and PI3K (LY294002) to elucidate pathway involvement. Results: Using G-LISA we determined that stimulation of primary chondrocytes with TGF? activates RhoA. Reciprocally, inhibition of RhoA/ROCK but not other signalling pathways prevents modification of the actin cytoskeleton in responseto TGF?. Inhibition of MEK/ERKsignaling rescued suppression of anabolic gene expression by TGF? including SOX9 mRNA and protein levels. Inhibition of MEK/ERK, Rho/ROCK, p38 MAPK and PI3K signalling pathways differentially controlled the induction of MMP13 and TNF? gene expression. TGF? also induced expression of CCL2 specifically through MEK/ERK activation. In turn, CCL2 treatment induced the expression of MMP3 and TNF?. Finally, we assessed cartilage degradation by immunohistochemical detection of type II collagen cleavage fragments generated by MMPs. Blockade of RhoA/ROCK and MEK/ERK signalling pathways reduced the generation of type IIcollagen cleavage fragments in response to TGF? stimulation. Conclusions: Rho/ROCK signalling mediates TGF?-induced changes inchondrocyte morphology, while MEK/ERK signalling mediates the suppression ofSox9 and its target genes, and CCL2 expression. CCL2, in turn, induces the expression of MMP3 and TNF?, two potent catabolic factors known to be involved in OA. These pathways may represent strategic targets for interventional approaches to treating cartilage degeneration in osteoarthritis. References: 1. Appleton CTG et al. Arthritis Rheum 2007;56:1854-68. 2. Appleton CTG et al. Arthritis Rheum 2007; 56:3693-705.
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Detmar, M., L. F. Brown, K. P. Claffey, K. T. Yeo, O. Kocher, R. W. Jackman, B. Berse, and H. F. Dvorak. "Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis." Journal of Experimental Medicine 180, no. 3 (September 1, 1994): 1141–46. http://dx.doi.org/10.1084/jem.180.3.1141.
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Psoriatic skin is characterized by microvascular hyperpermeability and angioproliferation, but the mechanisms responsible are unknown. We report here that the hyperplastic epidermis of psoriatic skin expresses strikingly increased amounts of vascular permeability factor (VPF; vascular endothelial growth factor), a selective endothelial cell mitogen that enhances microvascular permeability. Moreover, two VPF receptors, kdr and flt-1, are overexpressed by papillary dermal microvascular endothelial cells. Transforming growth factor alpha (TGF-alpha), a cytokine that is also overexpressed in psoriatic epidermis, induced VPF gene expression by cultured epidermal keratinocytes. VPF secreted by TGF-alpha-stimulated keratinocytes was bioactive, as demonstrated by its mitogenic effect on dermal microvascular endothelial cells in vitro. Together, these findings suggest that TGF-alpha regulates VPF expression in psoriasis by an autocrine mechanism, leading to vascular hyperpermeability and angiogenesis. Similar mechanisms may operate in tumors and in healing skin wounds which also commonly express both VPF and TGF-alpha.
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Armstead, W. M., R. Mirro, S. L. Zuckerman, M. Shibata, and C. W. Leffler. "Transforming growth factor-beta attenuates ischemia-induced alterations in cerebrovascular responses." American Journal of Physiology-Heart and Circulatory Physiology 264, no. 2 (February 1, 1993): H381—H385. http://dx.doi.org/10.1152/ajpheart.1993.264.2.h381.
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We observed previously that 20 min of global cerebral ischemia followed by 45 min of reperfusion selectively blocked cerebral vasodilation to hypercapnia and hypotension. This study determines the effects of pretreatment with transforming growth factor-beta (TGF-beta) on cerebrovascular responses after cerebral ischemia in piglets equipped with closed cranial windows. Hypercapnia-induced pial arteriolar dilation was blocked after cerebral ischemia (20 +/- 1 vs. 2 +/- 1% dilation before and after ischemia, respectively). Similarly, the increases in periarachnoid cortical cerebrospinal fluid 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and prostaglandin E2 (PGE2) concentration in response to hypercapnia were blocked (2.5 +/- 0.2- vs. 0.2 +/- 0.4-fold and 2.1 +/- 0.1- vs. 0.3 +/- 0.4-fold increase in 6-keto-PGF1 alpha and PGE2, respectively). Treatment with topical TGF-beta (400 ng/ml) before and during ischemia-reperfusion attenuated the loss of hypercapnia-induced cerebrovascular dilation (20 +/- 1 vs. 14 +/- 1% dilation before and after ischemia, respectively) and the loss of associated changes in cerebrospinal fluid prostanoids (2.0 +/- 0.2- vs. 1.7 +/- 0.2-fold and 2.3 +/- 0.2- vs. 2.2 +/- 0.3-fold increase in 6-keto-PGF1 alpha and PGE2 before and after ischemia, respectively). The loss of cerebrovascular dilation in response to hemorrhagic hypotension after ischemia was similarly prevented by TGF-beta. Cerebrovascular dilation to topical isoproterenol was unchanged after ischemia. TGF-beta may preserve endothelial cell function. We conclude that topical TGF-beta can attenuate cerebromicrovascular compromise caused by ischemia-reperfusion in newborn pigs.
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Ranges, G. E., I. S. Figari, T. Espevik, and M. A. Palladino. "Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha." Journal of Experimental Medicine 166, no. 4 (October 1, 1987): 991–98. http://dx.doi.org/10.1084/jem.166.4.991.
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The immunoregulatory effects of transforming growth factor beta (TGF-beta) and recombinant murine tumor necrosis factor alpha (rMuTNF-alpha) on CTL generation and activity were examined. The results demonstrate that TGF-beta, in a dose-dependent manner, inhibited CTL generation but not CTL activity. The inhibitory effects were detected only when TGF-beta was added within the first 48 h of the MLC. Little activity was seen when it was added thereafter, including the addition of TGF-beta to the cytotoxicity assay. The production of TNF-alpha, which occurs during early phases of the MLC and which is inhibited in the presence of TGF-beta, appears to have an important regulatory role, as altering the levels of TNF-alpha in an MLC can significantly influence CTL development. The inhibitory effects of TGF-beta on the MLC can be significantly reversed by the addition of rMuTNF-alpha to the cultures. These results demonstrate that TGF-beta can inhibit MLC and subsequent CTL generation at early stages of the reaction, and such inhibition may involve the suppression of TNF-alpha production.
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Garcia, J. V., B. D. Gehm, and M. R. Rosner. "An evolutionarily conserved enzyme degrades transforming growth factor-alpha as well as insulin." Journal of Cell Biology 109, no. 3 (September 1, 1989): 1301–7. http://dx.doi.org/10.1083/jcb.109.3.1301.
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A single enzyme found in both Drosophila and mammalian cells is able to selectively bind and degrade transforming growth factor (TGF)-alpha and insulin, but not EGF, at physiological concentrations. These growth factors are also able to inhibit binding and degradation of one another by the enzyme. Although there are significant immunological differences between the mammalian and Drosophila enzymes, the substrate specificity has been highly conserved. These results demonstrate the existence of a selective TGF-alpha-degrading enzyme in both Drosophila and mammalian cells. The evolutionary conservation of the ability to degrade both insulin and TGF-alpha suggests that this property is important for the physiological role of the enzyme and its potential for regulating growth factor levels.
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Yang, Jun, Chun Chu, Biao Deng, Sai Liang Ding, Guang Hui Wang, Yong Zhang, and Zhi Hua Quan. "Cytotoxic Effects of Transforming Growth Factor-α Conjugated with Cytotoxin Saporin on Proliferating Vascular Smooth Muscle Cells." Advanced Materials Research 621 (December 2012): 182–87. http://dx.doi.org/10.4028/www.scientific.net/amr.621.182.
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Abstract Objective To testify the special cytotoxicity of TGF-alpha-SAP on proliferating vascular smooth muscle cells and endothelial cells. Methods Conjugation of saporin to TGF-alpha was accomplished after derivatization of saporin and TGF-alpha with N-succinimidyl-3 (2-pyridyldithio) proprionate and final purification of the conjugate was achieved within Eppendorf Centrifugal Filter Cytotoxicity assays were measured by cell count. The studies of influence of TGF-alpha-SAP on values of Thymidine and leucine incorporation into SMCs and ECs were measured by 3H-thymidine uptake and 3H-leucine uptake, respectively. and receptor competition studies of TGF-alpha-SAP are measured by adding excess TGF-alpha in SMCs exposed for TGF-SAP. Results Cytotoxicity assays testified TGF-alpha-SAP conjugate could inhibit remarkably proliferation of SMCs in culture. The values of thymidine of TGF-alpha-SAP group (10-9M and 10-7M) in comparison significantly decreased to 60.9% and 56.0% of the control group respectively, suggesting that cellular DNA synthesis obviously decreased as TGF-alpha-SAP was added. But Saporin did not affect cellular DNA synthesis at higher level. The rate of 3H-leucine incorporation of TGF-alpha-SAP group significantly decreased to 47.3% of the control group, suggesting that SMCs protein synthesis obviously decreased as TGF-alpha-SAP was added. But TGF-alpha-SAP at the same level did not affect DNA synthesis and protein synthesis of ECs compared with the control group. Conclusion The results indicated that TGF-alpha-SAP possesses the more effective cytotoxicity than Saporin and the more special citotoxicity on proliferating vascular smooth muscle cells than on proliferating endothelial cells. Key words：cytotoxicity;selective; Drug-eluting stents;proliferation;saporin