Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunohistochemistry and in situ and Northern blot hybridization were employed to determine temporal and spatial expression of transforming growth factor-beta 1 (TGF beta 1) in the mouse uterus during the periimplantation period. The polyclonal antisera anti-LC-(1-30) and anti-CC-(1-30), raised against two different preparations of a peptide corresponding to the amino-terminal 30 amino acids of TGF beta 1, were used for histochemical analyses because of their distinct staining patterns. Anti-LC shows intracellular staining, while staining by anti-CC is primarily extracellular. The colocalization of intracellular staining by anti-LC with in situ hybridization of TGF beta 1 mRNA in the luminal and glandular epithelia on days 1-4 of pregnancy (day 1 = vaginal plug) indicates that the epithelial cells are the primary sites of TGF beta 1 synthesis during the preimplantation period. On the other hand, staining of the extracellular matrix of the stroma by anti-CC during this period suggests an active accumulation of TGF-beta 1 that is synthesized in and secreted from the epithelia. While intracellular staining and accumulation of TGF-beta 1 mRNA in the epithelia were clearly evident on days 1-4, the extracellular staining showed temporal fluctuations. The clear extracellular staining of the stroma that was observed on day 1 was absent on day 2; moderate staining was again visualized in the stroma on day 3 and was markedly increased on day 4.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1990 Jul
PMID:Cell type-specific expression of transforming growth factor-beta 1 in the mouse uterus during the periimplantation period. 228 9

The influence of modulating circulating levels of epidermal growth factor (EGF) and transforming growth factor beta 1 (TGF-beta 1) on tumor growth was examined in a variety of mouse models. Removal of the EGF-rich submandibular gland from host mice failed to alter the growth of a variety of human tumor xenografts or a C3H mouse tumor. Infusion of EGF from Alzet minipumps raised circulating EGF levels. However, only the A549 human tumor xenograft showed any significant increase in growth in the presence of EGF infusion and this response was marginal. The growth of Wehi 3BD+ and A549 tumor lines in culture was inhibited by TGF-beta 1. The growth of these lines in vivo, however, was not significantly altered by the administration of TGF-beta 1 via a variety of routes.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:In vivo evaluation of epidermal growth factor and transforming growth factor beta 1 in mouse tumor models. 228 1

Three cysteine residues are located in the pro region of the transforming growth factor beta 1 (TGF-beta 1) precursor at amino acid positions 33, 223, and 225. Previous studies (Gentry, L. E., Lioubin, M. N., Purchio, A. F., and Marquardt, H. (1988) Mol. Cell. Biol. 8, 4162-4168) with purified recombinant TGF-beta 1 (rTGF-beta 1) precursor produced by Chinese hamster ovary (CHO) cells revealed that Cys-33 can form a disulfide bond with at least 1 cysteine residue in mature TGF-beta 1, contributing to the formation of a 90-110-kDa protein. We now show that Cys-223 and Cys-225 form interchain disulfide bonds. Site-directed mutagenesis was used to change these Cys codons to Ser codons, and mutant constructs were transfected into COS cells. Analysis of recombinant proteins by immunoblotting showed that by substituting Cys-33 the 90-110-kDa protein is not formed, and thus, more mature dimer (24 kDa) is obtained, corresponding to a 3- to 5-fold increase in biological activity. Substitution of Cys-223 and/or Cys-225 resulted in near wild-type levels of mature TGF-beta 1. Furthermore, cells transfected with plasmid coding for Ser at positions 223 and 225 expressed only monomeric precursor proteins and released bioactive TGF-beta 1 that did not require acid activation, suggesting that dimerization of the precursor pro region may be necessary for latency.
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PMID:Site-directed mutagenesis of cysteine residues in the pro region of the transforming growth factor beta 1 precursor. Expression and characterization of mutant proteins. 247 34

Transforming growth factor-beta 1 (TGF-beta 1) is capable of eliciting a myriad of biological responses associated with cellular proliferation, as well as effects unrelated to the control of cell growth. We examined the possible role of TGF-beta 1 in the differentiation of rat liver epithelial (RLE) cells in vitro and studied the cellular distribution of TGF-beta 1 transcripts and protein during in vivo differentiation of oval cells. Furthermore, we followed the cellular distribution of TGF-beta 1 transcripts and protein during chemical hepatocarcinogenesis. By using in situ hybridization and immunohistochemical techniques, we showed that both TGF-beta 1 transcripts and protein are localized in nonparenchymal cells in normal liver, are expressed in oval cells during very early stages of hepatocytic differentiation in vivo, and are exclusively expressed in the nontumorous mesenchymal cell compartment during hepatocarcinogenesis. Furthermore, we showed that TGF-beta 1 is capable of inducing differentiation of RLE cells in vitro consistent with early stages of hepatocytic lineage differentiation. Our data indicate that the RLE cells similar to the oval cells in vivo may be an epithelial progenitor cell for hepatocytic cell lineage in adult mammalian liver.
Mol Carcinog 1989
PMID:Role of TGF-beta in normal differentiation and oncogenesis in rat liver. 261 82

Transient transfection of simian COS cells with a recombinant plasmid encoding the human transforming growth factor TGF-beta 2 precursor protein results in the production of a latent, biologically inactive protein. Upon acidification, recombinant TGF-beta 2 exhibits full biological activity, including inhibition of mink lung epithelial cell growth, stimulation of anchorage-independent growth of murine embryonic fibroblasts, and competition for TGF-beta receptor binding. Further analysis of conditioned media with antiserum to either a pro- [amino acid (aa) residues 1-220] or mature [aa 297-414] peptide of the TGF-beta 2 precursor suggests that TGF-beta 2, similar to TGF-beta 1 production in Chinese hamster ovary cells [Gentry et al., Mol. Cell. Biol. 7 (1987) 3418-3427], is initially synthesized as a larger precursor protein which is proteolytically cleaved to yield the mature 112-aa transforming growth factor.
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PMID:Transient production and secretion of human transforming growth factor TGF-beta 2. 262 79

The role of glycosylation of the transforming growth factor-beta 1 (TGF-beta 1) precursor was investigated by treating a transfected Chinese hamster ovary (CHO) cell line expressing high levels of recombinant TGF-beta 1 (TGF-beta 3-2000 cells) with a series of glycosylational inhibitors. Tunicamycin, a nucleoside antibiotic which prevents the formation of the dolichol intermediate necessary for oligosaccharide addition of the nascent polypeptide chain, appeared to block secretory exit and led to an increase in the cellular associated, nonglycosylated pro-TGF-beta 1 form. 1-Deoxymannojirimycin and swainsonine, inhibitors of the mannosidases I and II, respectively, blocked complete glycoprotein processing of the TGF-beta 1 precursor as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by sensitivity to glycosidases. However, the abnormal TGF-beta 1 polypeptides containing the altered carbohydrate side chains were secreted readily by the CHO cells. In contrast, inhibitors of the glucosidases at the first step in glycoprotein remodeling, 1-deoxynojirimycin and castanospermine, markedly inhibited secretion of the TGF-beta 1 polypeptides from transfected CHO cells. In all cases, these inhibitors did not appear to affect proteolytic processing of the TGF-beta 1 polypeptides. Furthermore, inhibitor treatment did not affect mannose-6-phosphorylation of the TGF-beta 1 polypeptides. These results suggest that glycosylation and early stage remodeling of oligosaccharide side chains are necessary for secretion of TGF-beta 1. Treatment of the transfected CHO cells with weak bases (NH4Cl and chloroquine), or a monovalent ionophore (monensin), prevented proteolytic processing of the TGF-beta 1 precursor indicating that cleavage occurs by proteases in an acidic cellular compartment.
Mol Endocrinol 1989 Jul
PMID:Transforming growth factor beta 1: importance of glycosylation and acidic proteases for processing and secretion. 267 79

Murine transforming growth factor-beta 2 (TGF-beta 2) cDNAs were isolated from cDNA libraries derived from a differentiated murine embryonic carcinoma cell line, PCC3. The composite cDNA sequence is 4267 nucleotides long, including a 1217 nucleotides 5'-untranslated sequence, and encodes a murine TGF-beta 2 precursor of 414 amino acids with 96% identity to its human counterpart. Several consensus polyadenylation sequences are present in the 1807 nucleotides 3'-untranslated sequence. Five TGF-beta 2 mRNA species are observed in the developing mouse fetus and they show different patterns of expression during development. TGF-beta 2 mRNA expression was also examined in adult mouse tissues, in which four of the five RNA species were observed. TGF-beta 2 mRNAs were present in all adult mouse tissues examined, except liver, and was most abundant in placenta, the male submaxillary gland and lung. The patterns of expression suggest a physiological role for TGF-beta 2 both in embryonic development and in the maintenance of adult tissues.
Mol Endocrinol 1989 Jul
PMID:Murine transforming growth factor-beta 2 cDNA sequence and expression in adult tissues and embryos. 279 4

Several tumor promoters exert their effects by activating a Ca2+-phospholipid-dependent protein kinase (protein kinase C). To study the role of this protein kinase in the regulation of Sertoli cell function, we have evaluated the effect of phorbol esters, mezerein, and teleocidin on the response of the Sertoli cell to FSH. Cells were treated for different time intervals with the tumor promoters, and cell response was measured by stimulating the cell with FSH. 12-O-Tetradecanoylphorbol 13-acetate (TPA) had no significant effect on basal cAMP production but markedly inhibited the cAMP response to FSH. Significant inhibition of cAMP accumulation was observed after 15 min treatment with 100 nM TPA, and maximal inhibition developed within 1 h. The decrease in cAMP accumulation was dependent on the dose of phorbol ester used, with an estimated ED50 of 10-20 nM TPA. In a manner similar to TPA, mezerein and teleocidin also inhibited the cAMP response of the Sertoli cell, while the phorbol ester 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), inactive as a tumor promoter and unable to stimulate protein kinase C activity, was devoid of effect. The promoters that inhibited cAMP response also inhibited the FSH-stimulated androgen aromatization. The dose of TPA producing half-maximal inhibition of estrogen accumulation was again 10-20 nM TPA, mezerein, and teleocidin inhibited estrogen accumulation whether FSH, forskolin or cholera toxin was used to stimulate the Sertoli cell. In contrast, only FSH-dependent cAMP accumulation was inhibited by the tumor promoters, while forskolin and cholera toxin stimulations were not affected. These data suggest that tumor promoters which activate protein kinase C act at two sites of the Sertoli cell response. They alter receptor-mediated signal transduction across the membrane and affect steroidogenesis at a site distal to cAMP accumulation.
Mol Cell Endocrinol 1987 Feb
PMID:Inhibition by phorbol esters and other tumor promoters of the response of the Sertoli cell to FSH: evidence for dual site of action. 303 Aug 55

Analyses of cDNA clones coding for simian type 1 transforming growth factor beta (TGF-beta 1) suggest that there are three potential sites for N-linked glycosylation located in the amino terminus of the precursor region. Analysis of [3H]glucosamine-labeled serum-free supernatants from a line of Chinese hamster ovary cells which secrete high levels of recombinant TGF-beta 1 indicate that the TGF-beta 1 precursor, but not the mature form, is glycosylated. Digestion with neuraminidase resulted in a shift in migration of the two TGF-beta 1 precursor bands, which suggests that they contain sialic acid residues. Endoglycosidase H had no noticeable effect. Treatment with N-glycanase produced two faster-migrating sharp bands, the largest of which had a molecular weight of 39 kilodaltons. TGF-beta 1-specific transcripts produced by SP6 polymerase programmed the synthesis of a 42-kilodalton polypeptide which, we suggest, is the unmodified protein backbone of the precursor. Labeling with 32Pi showed that the TGF-beta 1 precursor was phosphorylated in the amino portion of the molecule.
Mol Cell Biol 1988 May
PMID:Recombinant type 1 transforming growth factor beta precursor produced in Chinese hamster ovary cells is glycosylated and phosphorylated. 316 41

Recently, the simian type 1 transforming growth factor beta (TGF-beta 1) cDNA was expressed at high levels in Chinese hamster ovary (CHO) cells by dihydrofolate reductase-induced gene amplification (L.E. Gentry, N.R. Webb, G.J. Lim, A.M. Brunner, J.E. Ranchalis, D.R. Twardzik, M.N. Lioubin, H. Marquardt, and A.F. Purchio, Mol. Cell. Biol. 7:3418-3427, 1987). We have now purified and characterized the recombinant proteins released by these cells. Analyses of the precursor proteins by amino acid sequencing identified potentially important proteolytic processing sites. Signal peptide cleavage occurs at the Gly-29-Leu-30 peptide bond of pre-pro-TGF-beta 1, yielding pro-TGF-beta 1 (30 to 390). In addition, proteolytic processing of the precursor to yield mature TGF-beta 1 occurs at the dibasic cleavage site immediately preceding Ala-279, indicating that CHO cells possess the appropriate processing enzyme. Greater than 95% of the biological activity detected in the conditioned medium of the CHO transfectant was due to mature, properly processed growth factor. Highly purified recombinant TGF-beta 1 had the same specific biological activity as natural TGF-beta 1. The concentration of TGF-beta 1 required for half-maximal inhibition of Mv1Lu mink lung epithelial cell growth was approximately 1 to 2 pM. Purified precursor inhibited mink lung cell proliferation at 50 to 60 pM concentrations. The purified precursor preparation was shown to consist of pro-TGF-beta 1 (30 to 390), the pro region of the precursor (30 to 278), and mature TGF-beta 1 (279 to 390) interlinked by at least one disulfide bond with the pro portion of the precursor. These recombinant forms of TGF-beta1 should prove useful for further structural and functional studies.
Mol Cell Biol 1988 Oct
PMID:Molecular events in the processing of recombinant type 1 pre-pro-transforming growth factor beta to the mature polypeptide. 318 45


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