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Hepatocytes can be maintained in culture for periods of a few hours to many days. This review summarizes the metabolic characteristics of these cultures and describes their use in studying the regulation of plasma protein synthesis. Hormones selectively stimulate the synthesis of certain proteins. Cortisol stimulates the synthesis of fibrinogen and other acute-phase proteins; whereas, insulin stimulates albumin synthesis. In the latter case insulin increases the rate of a nuclear process. Mediators elaborated by leukocytes stimulate acute-phase protein synthesis in hepatocytes. Plasmin-generated fibrin peptides stimulate fibrinogen synthesis via a leukocytic mediator. Lipoprotein synthesis is stimulated by fatty acids and is inhibited by albumin and other macromolecules. These and other processes are susceptible to detailed analysis using sub-cellular fractions (mRNA, nuclei, transcription factors, etc.) isolated from hepatocytes. Studies on fetal or embryonic hepatocytes and hepatomas are yielding information on the regulation of secretory protein synthesis during development and following neoplastic transformation.
Mol Cell Biochem 1983
PMID:Plasma protein induction by isolated hepatocytes. 619 22

The yeast SUC2 gene codes for the secreted enzyme invertase. A series of 16 different-sized gene fusions have been constructed between this yeast gene and the Escherichia coli lacZ gene, which codes for the cytoplasmic enzyme beta-galactosidase. Various amounts of SUC2 NH2-terminal coding sequence have been fused in frame to a constant COOH-terminal coding segment of the lacZ gene, resulting in the synthesis of hybrid invertase-beta-galactosidase proteins in Saccharomyces cerevisiae. The hybrid proteins exhibit beta-galactosidase activity, and they are recognized specifically by antisera directed against either invertase or beta-galactosidase. Expression of beta-galactosidase activity is regulated in a manner similar to that observed for invertase activity expressed from a wild-type SUC2 gene: repressed in high-glucose medium and derepressed in low-glucose medium. Unlike wild-type invertase, however, the invertase-beta-galactosidase hybrid proteins are not secreted. Rather, they appear to remain trapped at a very early stage of secretory protein transit: insertion into the endoplasmic reticulum (ER). The hybrid proteins appear only to have undergone core glycosylation, an ER process, and do not receive the additional glycosyl modifications that take place in the Golgi complex. Even those hybrid proteins containing only a short segment of invertase sequences at the NH2 terminus are glycosylated, suggesting that no extensive folding of the invertase polypeptide is required before initiation of transmembrane transfer. beta-Galactosidase activity expressed by the SUC2-lacZ gene fusions cofractionates on Percoll density gradients with ER marker enzymes and not with other organelles. In addition, the hybrid proteins are not accessible to cell-surface labeling by 125I. Accumulation of the invertase-beta-galactosidase hybrid proteins within the ER does not appear to confer a growth-defective phenotype to yeast cells. In this location, however, the hybrid proteins and the beta-galactosidase activity they exhibit could provide a useful biochemical tag for yeast ER membranes.
Mol Cell Biol 1984 Nov
PMID:Invertase beta-galactosidase hybrid proteins fail to be transported from the endoplasmic reticulum in Saccharomyces cerevisiae. 644 5

Adenohypophysial sulfated and glycosylated polypeptides were studied by high-resolution two-dimensional polyacrylamide-gel electrophoresis followed by fluorography. The preparations analyzed were the following: (a) homogenates from cow and rat anterior pituitary slices labeled in vitro either with [35S]sulfate or D-[6-3H]glucosamine; (b) materials released from bovine adenohypophysis slices pulse labeled with [35S]sulfate; and (c) purified fractions of bovine prolactin granules stripped by detergent treatment of their limiting membrane. A heterogeneous family of sulfated components, almost all glycosylated, differing in their peptide moieties as well as in their isoelectric points, was revealed in the glandular tissue. The major of these components (apparent Mr approximately 70 000; pI approximately 4.8), which was also highly labeled by L-[3H]-leucine (Zanini, A., and Rosa, P. (1981) Mol. Cell. Endocrinol. 24), might be a secretory protein because it accumulates in the medium during chase incubation of bovine pituitary slices in vitro. This sulfated component, which was more concentrated in the bovine than in the rat gland, was present in purified bovine prolactin granules stripped of their limiting membrane. However, the available evidence suggests that this might not be the only subcellular location of the sulfated polypeptide in the pituitary tissue.
Mol Cell Endocrinol 1981 Nov
PMID:Characterization of adenohypophysial polypeptides by two-dimensional gel electrophoresis. II. Sulfated and glycosylated polypeptides. 729 61

The Saccharomyces cerevisiae KRE1 gene encodes a secretory protein required for the production of the cell wall polymer (1-->6)-beta-glucan. Here we report further characterization of the KRE1 gene product, Kre1p. A functional, epitope-tagged Kre1p is shown to be highly modified in a SEC53-dependent manner. Kre1p is O-glycosylated, but the basis for the majority of its post-translational modification is unknown. Fractionation of Kre1p reveals a cell wall-associated form and a less abundant membrane-associated species. Indirect immunoflurorescence demonstrates that Kre1p localizes to the cell surface, where it becomes concentrated at the surface of mother cells. Such a localization of Kre1p seems to parallel the CAL1/CSD2-dependent cell wall deposition of chitin found in S. cerevisiae, and is consistent with evidence from Schizophyllum commune that (1-->6)-beta-glucan accumulates during maturation of the subapical region of the wall distal to the hyphal tip.
Mol Gen Genet 1995 Nov 15
PMID:Yeast Kre1p is a cell surface O-glycoprotein. 750 Sep 43

The filamentous hemagglutinin (FHA) of Bordetella pertussis is an adhesin that binds the bacteria to cells of the respiratory epithelium in whooping-cough infections. Mature FHA is a 220 kDa secretory protein that is highly immunogenic and has been included in acellular vaccines. We have investigated its structure by combining electron microscopy and circular dichroism spectroscopy (CD) with computational analysis of its amino acid sequence. The FHA molecule is 50 nm in length and has the shape of a horseshoe nail: it has a globular head that appears to consist of two domains; a 35 nm-long shaft that averages 4 nm in width, but tapers slightly from the head end; and a small, flexible, tail. Mass measurements by scanning transmission electron microscopy establish that FHA is a monomer. Its sequence contains two regions of tandem 19-residue pseudo-repeats: the first, of 38 cycles, starts at residue 344; the second, of 13 cycles, starts at residue 1440. The repeat motifs are predicted to consist of short beta-strands separated by beta-turns, and secondary structure measurements by CD support this prediction. We propose a hairpin model for FHA in which the head is composed of the terminal domains; the shaft consists mainly of the repeat regions conformed as amphipathic, hyper-elongated beta-sheets, with their hydrophobic faces apposed; and the tail is composed of the intervening sequence. Further support for the model was obtained by immuno-labeling electron microscopy. The 19-residue repeats of FHA have features in common with the leucine-rich repeats (LRRs) that are present in many eukaryotic proteins, including some adhesion factors. The model is also compared with the two other classes of filamentous proteins that are rich in beta-structure, i.e. viral adhesins and two beta-helical secretory proteins. Our proposed structure implies how the functionally important adhesion sites and epitopes of FHA are distributed: its tripeptide (RGD) integrin-binding site is assigned to the tail; the putative hemagglutination site forms part of the head; and two classes of immunodominant epitopes are assigned to opposite ends of the molecule. Possible mechanisms are discussed for two modes of FHA-mediated adhesion.
J Mol Biol 1994 Aug 05
PMID:Filamentous hemagglutinin of Bordetella pertussis. A bacterial adhesin formed as a 50-nm monomeric rigid rod based on a 19-residue repeat motif rich in beta strands and turns. 751 81

Human endometria were analysed for the synthesis and secretion of proteins following short term culture of human endometrial tissue in the presence of 35S-methionine. During the menstrual cycle secretory proteins of molecular weight (MW) 30, 35, 45, 50, 59, 74, 97 and 135 kDa showed increased synthesis during the proliferative phase. The synthesis of these proteins decreased in the secretory phase but the induction of a 26 kDa protein in the early secretory phase and a 28 kDa protein in the late secretory phase was observed. The synthesis of the above secretory proteins of the human endometrium was also confirmed by two dimensional gel electrophoresis. Further, the results demonstrated that the secretory protein profile of human decidual endometria and endometria exhibiting irregular ripening was identical to that of normal secretory phase endometria. But, endometria exhibiting hyperplasia, cystic glandular hyperplasia and adenomatous glandular hyperplasia presented similar secretory protein profiles which were identical with the secretory protein profile of normal proliferative phase endometrium. The present study confirms that a number of proteins are synthesised by the human endometrium during the normal menstrual cycle and during pregnancy. It also provides data for the first time on the proteins secreted by the endometria exhibiting irregular ripening, hyperplasia, cystic glandular hyperplasia and adenomatous glandular hyperplasia.
Cell Mol Biol (Noisy-le-grand) 1995 Jun
PMID:Synthesis and secretion of proteins by the human proliferative, secretory, decidual and hyperplastic endometrium. 754 92

Calcitonin gene-related peptide (CGRP) immunoreactivity is found in the airways in terminals of primary sensory afferents, in neuroendocrine cells, and in tracheal serous cells. This study shows that rat alveolar epithelial cells express immunoreactive CGRP also. Freshly isolated cells contained 34 +/- 23 fmol CGRP/10(7) cells (n = 4). Cultured type II cells secreted CGRP at a stable rate for 3 days after cell isolation, averaging 206 +/- 14 fmol CGRP/well/day (750,000 cells plated/well with approximately 30% efficiency). The extracellular CGRP immunoreactivity eluted in the same fraction as rat CGRP-beta on high performance liquid chromatography. Secretion of CGRP from type II cells was reversibly blocked by monensin, an inhibitor of secretory protein transport. CGRP secretion was stimulated in a concentration-dependent fashion by phorbol myristate acetate, but it was not affected by forskolin, capsaicin, bradykinin, or nicotine. CGRP was not detected in culture media from alveolar macrophages or fibroblasts, potential contaminants of primary type II cell cultures. Calcitonin is expressed by neuroendocrine cells, but it was not detected in conditioned media from type II cell cultures. Thus, type II alveolar epithelial cells express and secrete CGRP. Secretion occurs constitutively and is regulated by a protein kinase C-dependent pathway. Secretion is unaffected by increases in cyclic adenosine monophosphate or by treatments that induce release of CGRP from sensory afferent nerve terminals in the airways.
Am J Respir Cell Mol Biol 1995 Nov
PMID:Expression of calcitonin gene-related peptide by cultured rat alveolar type II cells. 757 92

The process of insertion into and translocation across the ER membrane is a significant step in the biosynthesis of a membrane or secretory protein. This commits the protein to a destination within the "secretory pathway" (Palade, 1975) and is part of a complex series of events involving protein targeting, translocation, maturation and sorting, which finally results in a biologically-active protein being delivered to its correct subcellular location. The focus for this review has been the initial events of this process. Proteins which constitute at least a part of the actual translocation site across the ER membrane have been identified and the minimum components required to reconstitute ER translocation in vitro have been defined. A detailed description of the architecture of the ER translocation site and the molecular events occurring during translocation and membrane insertion remain goals for the future. The process occurring in vivo may be more complex since (i) each translocation site may only promote a single round of translocation in vitro whereas in vivo the sites must operate catalytically and go through many cycles of translocation and insertion (see Gilmore, 1993) and (ii) the in vivo requirement for a translocation site which is impermeable to small molecules (in order not to dissipate chemical gradients and the redox potential) is unlikely to be important for in vitro assays. Thus, other components which play a vital role in protein translocation and membrane insertion in vivo may remain to be identified. Our future aim must be to place a detailed understanding of the molecular events of the translocation process into the context of the normal cellular environment.
Prog Biophys Mol Biol 1995
PMID:Protein translocation at the membrane of the endoplasmic reticulum. 762 79

We recently described the establishment and the characterization of two rat endometrial adenocarcinoma cell lines which we called RUCA-I and RUCA-II. Despite fairly high estrogen receptor levels neither cell line responded to estradiol in conventional cell culture conditions on plastic and in the presence of serum. A limited hormonal response to the antiestrogen tamoxifen was detectable in RUCA-I but not in RUCA-II cells. To advance our cell culture conditions we plated RUCA-I cells on a layer of reconstituted basement membrane (Harbor Matrix) in the presence of a serum-free defined medium. These cell culture conditions induced hormone responsiveness of RUCA-I cells and permitted a stimulation of proliferation by estradiol. Further, two estradiol-induced secretory proteins with an apparent molecular weight of 115 kD and 60 kD could be identified by SDS-gelelectrophoresis if analyzed under reducing conditions. These proteins migrated as a single band in a non-reducing electrophoresis gel and were identified as components of the complement C3 system. Additionally, our results suggest that the effects of extracellular matrix and hormones on the expression of these proteins are additive. We conclude that processes of functional differentiation are most likely to occur in this in vitro model, particularly since the expression of components of the complement C3 system was under estrogenic control. Complement C3 proteins represent major estradiol-inducible secretory protein of the immature rat uterus in vivo. Culturing RUCA-I cells on top of a layer of reconstituted basement membrane provides a novel tool to study the importance of the extracellular environment on the hormone-induced gene expression in endometrial carcinogenesis in vitro.
J Steroid Biochem Mol Biol 1995 Mar
PMID:Extracellular matrix induces hormone responsiveness and differentiation in RUCA-I rat endometrial adenocarcinoma cells. 769 47

Using sequential HPLC and capillary electrophoresis (CE), testibumin (CMB-1) has been purified to apparent homogeneity from Sertoli cell-enriched culture medium prepared from 20-day-old rat testes. N-Terminal amino acid sequence analysis of the purified testibumin revealed a partial sequence of NH2-XPVQDPKI. When this partial sequence was compared to existing protein database, it was shown that it is identical to a previously isolated Sertoli cell secretory protein, sulfated glycoprotein I (SGP-1). The fact that testibumin is equivalent to SGP-1 was further confirmed when its full-length cDNA was isolated and sequenced. Studies using quantitative PCR to examine the changes of steady-state mRNA level of testibumin (SGP-1) in the rat testes between 3 and 60 days of age indicated that its mRNA increased rapidly after birth, peaked at 10-20 days, and declined rapidly where the adult testibumin mRNA level was similar to the neonatal rat at 3 days of age. Depletion of germ cells by a single dose of lonidamine, an antispermatogenic drug, did not induce an increase in testibumin (SGP-1) mRNA level indicating its mRNA expression is not dependent on germ cells.
Biochem Mol Biol Int 1994 Nov
PMID:Rat testicular testibumin is identical to sulfated glycoprotein-1 (SGP-1) whose mRNA expression in the testis is age- but not germ cell-dependent. 770 2


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