Robert R. Friis's research while affiliated with Universität Bern and other places

Publications (144)

Article
Secreted frizzled-related protein 4 (sFRP4) blocks the Wnt signalling pathway by competitively binding Wnt ligands (frizzled receptors). This pathway is important during development and oncogenesis. It is, however, complex with a large number of interacting proteins, isoforms and receptors. The Wnt signalling pathway has a role in human placental d...
Article
Serous ovarian cancer is the most prevalent type of ovarian cancer. The majority of women present at an advanced stage and patient survival is poor. Resistance to chemotherapy is thought to relate to failure of tumours to undergo apoptosis. Secreted frizzled-related protein 4 (SFRP4) has been demonstrated to be involved in apoptosis in the ovary bu...
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Conserved Wnt ligands are critical for signalling during development; however, various factors modulate their activity. Among these factors are the Secreted Frizzled-Related Proteins (SFRP). We previously isolated the SFRP-4 gene from an involuting rat mammary gland and later showed that transgenic mice inappropriately expressing SFRP-4 during lact...
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Abnormal alveolar wound repair contributes to the development of pulmonary fibrosis after lung injury. Hepatocyte growth factor (HGF) is a potent mitogenic factor for alveolar epithelial cells and may therefore improve alveolar epithelial repair in vitro and in vivo. We hypothesized that HGF could increase alveolar epithelial repair in vitro and im...
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Induction of protein expression in a tissue-specific manner by gene transfer over-expression techniques has been one means to define the function of a protein in a biological paradigm. Studies with retinoid reporter constructs transfected in mammary cell lines suggests that lactoferrin (Lf) affects retinoid signaling pathways and alters apoptosis....
Article
The corpus luteum (CL) is a temporary organ involved in the maintenance of pregnancy. In the course of its life-cycle, the CL undergoes two distinct and consecutive processes for its inevitable removal through apoptosis: functional and structural luteolysis. We isolated a gene encoding for a novel rat zinc finger protein (ZFP), named rat ZFP96 (rZF...
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Secreted frizzled-related protein-4 (sFRP-4) belongs to a family of soluble proteins that have a Frizzled-like cysteine-rich domain and function as modulators of Wnt-Frizzled (Fz) signals. As several Wnts and Fz are expressed at defined stages of follicular development in rodent ovaries, these studies were undertaken to evaluate the hormone-regulat...
Article
Ovulation is a complex, multi-factorial event that involves the degeneration of a specific area of the follicular and ovarian surface via apoptosis. Many apoptosis related genes have been identified in the ovary. Secreted Frizzled Related Protein 4 (sFRP4) is a protein that appears to antagonize a molecular pathway for cell survival. sFRP4 gene exp...
Article
We sought to investigate the role inhibitor of apoptosis proteins (IAPs) play in the life cycle of the corpus luteum (CL) of the rat. We isolated two clones with amino acid homology to rat IAP2 (BIRC 3) and three to rat IAP3 (rIAP3; BIRC 4). The expression of rIAP3 mRNA was examined in the rat CL during and after pregnancy, in Day 8 pregnant rats a...
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Using differential display, we isolated DDC-4, a secreted frizzled-related protein (sFRP), which is induced in the physiological apoptosis of hormonally regulated, reproductive tissues such as mammary gland, prostate, corpus luteum and uterus. The role of this gene in apoptosis was studied in animals overexpressing ectopic DDC-4/sFRP-4. Transgenic...
Article
Milk ejection and milk removal is considerably influenced by the sympathetic nervous system. Stimulation of α-adrenergic receptors by administration of α-adrenergic agonists inhibits alveolar milk ejection and milk removal in dairy cows due to smooth muscle contraction (Blum et al. 1989; Bruckmaier et al. 1991). However, contraction of the teat in...
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Tissue transglutaminase (tTG) is upregulated in various cells undergoing apoptosis. To investigate the transcriptional regulation of tTG a mouse strain carrying a beta-galactosidase reporter gene under the control of a 3.8 kilobase fragment of the tTG promoter was characterised. The transgene construct was shown to be expressed in the apoptotic reg...
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Physiological apoptosis in mammals is a type of programmed cell death, an important element in the developmental repertoire ensuring tissue homeostasis and proper disposal of cells that are no longer needed, such as milk-producing epithelial cells in the mammary gland after lactation, luteal cells in the post partum Corpus luteum or secretory cells...
Article
A strong and coordinated upregulation of the glycolytic, glutaminolytic and pentose phosphate pathway enzymes occurs during the onset of lactation in the normal mouse mammary gland. Induction of apoptosis by removing the pups led to an inactivation of the same enzymes with different time courses. While the ATP-consuming glycolytic 6-phosphofructo 1...
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To study mammary gland expression of the epithelium-restricted Ets factor, ESX, mouse cDNA and genomic sequences were cloned and a approximately 350 bp proximal promoter region with >80% mouse-human homology was identified that mediates ESX induction by serum, heregulin (HRG), or epidermal growth factor (EGF). ESX mRNA expression progressively incr...
Article
The involution of the corpus luteum (CL) at parturition is an example of physiological apoptosis, a complex process involving massive vascular regression while luteal cells undergo apoptosis. In the present study, changes in gene expression associated with physiological apoptosis were examined. Three genes isolated in our laboratory because of thei...
Chapter
Proliferating nonnal cells and tumor cells typically express a particular isoenzyme of pyruvate kinase called type M 2-PK. This isoenzyme exists in two different forms: the so-called tumor M 2-PK, which is strongly overexpressed in tumor cells, and the lung M 2-PK, which is the predominant species found in lung. The tumor M 2-PK mainly appears in a...
Article
The differential display method has been used in our laboratory as a coincidence analysis to isolate genes expressed in common in each of three different rat tissues undergoing physiological apoptosis: mammary gland, ovarian corpus luteum and ventral prostate. The most interesting of these isolates, DDC-4, shows a clear association with apoptosis,...
Article
Apoptosis plays a striking role in the hormone-dependent involution of the mammary gland, but it has proved difficult to distinguish between the 'cell death' associated genes and the 'tissue remodelling' genes which are expressed concurrently. To identify cell death-associated genes, we have established a 'coincidence analysis' based on the previou...
Article
Continuous milk production during lactation is dependent on a complex interplay of lactogenic hormones and the suckling stimulus exerted by the young. Involution can be initiated in the mouse mammary gland at any stage of lactation by removing the pups; involution then remains reversible for about 30 to 36 h. Involution in the mouse mammary gland i...
Article
Apoptosis is a form of cell death in which cellular integrity is maintained and neither cytoplasmic nor nuclear content is released. The Ca(2+)-dependent tissue transglutaminase (tTG) is an enzyme that forms protein cross-links between specific glutamyl and lysyl side-chains of intra- and extracellular proteins, therefore it may be responsible for...
Article
Normal development and maintenance of tissue size is dependent on a balance between cell proliferation and cell death. Apoptosis, or programmed cell death, plays important roles in mammary gland development, from the embryonic development of sexual dimorphism to senescent involution of the mammary gland. The involution of secretory epithelium follo...
Article
The death of secretory mammary epithelium that occurs during the postlactational involution of the mammary gland provides a normal physiological setting for studying apoptosis during an important developmental process. Understanding the cascade of gene expression and subsequent protein interactions that result both in the death of secretory mammary...
Article
Although apoptosis is important in determining cell fate and maintaining tissue homeostasis, the initiation and control of apoptotic cell death in epithelium is not well understood. Post-lactationai involution of the mammary gland provides both an important developmental process and a normal physiological setting for studying apoptosis of epitheliu...
Article
In an effort to develop a suitable bioassay for testing lung growth factors that might be operative during compensatory lung growth following partial pneumonectomy, a simple and inexpensive lung organ culture system was characterized. The culture employs lung tissue slices obtained by means of a device allowing thicknesses of 500 microns to be cut...
Article
Understanding the cascade of gene expression and subsequent protein interactions that result both in the death of secretory mammary epithelium and the remodeling and renewal of the mammary gland for another cycle of lactation poses significant challenges (see Chapters 7 and 8, this volume). The complexity of mammary gland involution warrants cautio...
Chapter
The massive cell death of secretory epithelium in the mammary gland following each cycle of pregnancy/lactation offers an especially convenient model for studies on the biochemistry of programmed cell death. Programmed cell death in the mammary gland takes the form of an apoptosis (Walker et al., 1989; Strange et al., 1992). Few examples of in vivo...
Article
The mammary gland, during post-lactational involution, is subjected to extensive tissue reconstruction. This process is governed by the concerted expression of extracellular-matrix-degrading enzymes and their inhibitors. During carcinogenesis, the invasive growth of tumor cells is characterized by the penetration of the basement membrane and stroma...
Article
Mammary epithelial cells terminally differentiate in response to lactogenic hormones. We present evidence that oncoprotein overexpression is incompatible with this hormone-inducible differentiation and results in striking cellular morphological changes. In mammary epithelial cells in culture, lactogenic hormones (glucocorticoid and prolactin) activ...
Article
Mammary epithelial cells terminally differentiate in response to lactogenic hormones. We present evidence that oncoprotein overexpression is incompatible with this hormone-inducible differentiation and results in striking cellular morphological changes. In mammary epithelial cells in culture, lactogenic hormones (glucocorticoid and prolactin) activ...
Article
During the in vitro differentiation of HL60 cells tyrosine-specific kinases are activated. The expression of lyn, a src-related tyrosine kinase, was studied by analysis of the steady-state levels of its transcript during the cell differentiation process induced by retinoic acid, phorbol 12-myristate 13-acetate and 1,25-dihydroxyvitamin D3. In contr...
Article
During post-lactational mammary gland involution, the bulk of mammary epithelium dies and is reabsorbed. This massive cell death and tissue restructuring was found to be accompanied by a specific pattern of gene expression. Northern blot analysis showed that weaning resulted in a dramatic drop in ODC, a gene involved in synthesis of a component of...
Article
As a common characteristic of tumor cells, as well as of normal proliferating cells in the G1-phase of cell cycle, one finds constitutive high levels of all the glycolytic metabolites arising between glucose 6-phosphate and phosphoenolpyruvate. Thus, it is that the phosphometabolites fructose 1,6-bisphosphate, ribose 5-P, P-ribose-PP, NAD, GTP, CTO...
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Mammary epithelial differentiation is the culmination of responses to a complex sequence of hormonal stimuli. An in vitro model for this process should retain the basic features of in vivo epithelial differentiation. The IM-2 mouse mammary cell line responds to lactogenic hormone stimulation by synthesizing the milk protein beta-casein. Epithelial...
Article
Protein tyrosine kinases (PTKs) play a central role in cellular regulation by virtue of their participation in, and control of, signal transduction pathways; they act as a molecular interface between the cell's environment and intercellular metabolism. The mammary gland, unlike most organs, undergoes most of its morphogenesis in juvenile and adult...
Article
The expression of myeloperoxidase was studied in three human myeloid leukemic cell lines. The myeloperoxidase transcript was strongly expressed in promyelocytic HL 60 cells, whereas much lower levels were detected in immature monocytic U 937 cells. Phorbol-12-myristate-13-acetate induction resulted in inhibition of myeloperoxidase expression within...
Article
We have analyzed morphological and biochemical changes occurring during megakaryocytic differentiation of the human chronic myelogenous leukemia cell line K562 induced by phorbol 12-myristate 13-acetate (PMA). PMA-treated cells became growth arrested, were slightly larger and irregular in shape, adhered better to the culture flask surface, and expr...
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The A431 human epidermoid carcinoma cell line exhibits a 30-100-fold overexpression of the epidermal growth factor (EGF) receptor. We have characterized a membrane-associated phosphotyrosyl-protein phosphatase (PTPase) in these cells since it seemed reasonable that overexpression of the EGF-receptor tyrosine kinase will be matched by high PTPase ac...
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We have previously described the inhibition of glucocorticoid-dependent transcription from the mouse mammary tumor virus long terminal repeat promoter by products of the H-ras and v-mos oncogenes. We have studied the effects of conditional oncogenes on expression of glucocorticoid-dependent indicator genes. Expression of the glucocorticoid-dependen...
Article
We have established and characterized a spontaneously immortalized, nontumorigenic mouse mammary cell line, designated IM-2. IM-2 cells synthesize large amounts of the milk protein beta-casein upon addition of lactogenic hormones. The induction of beta-casein occurs rapidly and does not require any exogenous extracellular matrix components. The IM-...
Article
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In order to study the hormonal regulation of gene expression in mammary epithelial cells, we isolated a prolactin-responsive cell clone, HC11, from the COMMA-1D mouse mammary epithelial cell line. Clone HC11 was selected as a unique example of a cloned mouse mammary epithelial cell which has no requirement for complex, exogenously added, extracellu...
Article
We have analysed the effects of oncogenic transformation on the expression of type VI collagen in mesenchymal cells. Synthesis of type VI collagen was almost completely inhibited in fibroblasts transformed by DNA or RNA tumour viruses or in cells derived from spontaneous mesenchymal tumours. Inhibition of type VI collagen synthesis appears, therefo...
Article
The v-mos oncogene was subjected to the transcriptional control of the MMTV LTR and introduced by transfection into NIH 3T3 cells. The LTR v-mos gene was induced by the addition of glucocorticoid hormone to the growth medium of cells synchronized by culturing in 1.5% FCS for 36 h. The effects of p37 v-mos expression were monitored. The endogenous c...
Article
We constructed a retroviral vector (pZSR) which is capable of simultaneously expressing the neomycin resistance gene and the viral ras oncogene. Primary mammary gland epithelial cells were prepared from mid-pregnant mice and infected with this virus. Cell lines with epithelial cell characteristics could be established with a low frequency. High exp...
Article
We have attempted to reverse the transformed phenotype of cells expressing the H-ras oncogene. A plasmid in which the first exon of the H-ras oncogene was coupled to the SV40 early promoter in an anti-sense orientation was constructed. This construct was introduced into a clone of H-ras-transformed NIH/3T3 cells. Simultaneous expression of both the...
Article
The endogenous cellular oncogene products, pp60c-src, exhibits a protein kinase activity, but is itself a phosphoprotein. Based on the assumption that pp60c-src might play a role in the control of cell proliferation, we have studied its behaviour as a substrate for phosphorylation known to occur when quiescent, serum-deprived cells are stimulated t...
Article
A new feline sarcoma virus designated Theilen-Pedersen (TP1-FeSV) has been isolated from a spontaneous, slowly growing fibrosarcoma of a domestic short-haired 4-year-old castrated cat. The virus codes for a gag-onc fusion protein of 83,000 molecular weight phosphorylated in vivo at serine, threonine, and tyrosine residues. Cells transformed in vitr...
Article
We have used the method of chemical crosslinking in order to determine the spatial interactions between components of Rous sarcoma virus. A high molecular weight complex formed by crosslinking has been isolated by ultracentrifugation on sucrose density gradients containing 0.1% (w/v) sodium dodecyl sulphate. This complex is composed of the two vira...
Article
An assay of adenosine(5')tetraphospho(5')adenosine (Ap4A), based on the luciferin/luciferase method for ATP measurement, was developed, which allows one to determine picomolar amounts of unlabeled Ap4A in cellular extracts. In eukaryotic cells this method yielded levels of Ap4A varying from 0.01 microM to 13 microM depending on the growth, cell cyc...
Article
Using chicken embryo fibroblasts infected with the NY68 transformation-defective temperature-sensitive mutant of Rous sarcoma virus, the phosphorylation and enzyme kinetic properties of enolase have been studied before, and at different stages after, the onset of transformation. A method for purification of enolase was developed, which minimized de...
Article
We have investigated the influence of 2',5' adenosine nucleotides on the replication and transformation of cells by Rous sarcoma virus (RSV). Treatment with the nucleotides ppp2',5'A4 and 2',5'A4 causes a striking reduction (50-fold) in the yield of infectious progeny virus, while ppp2',5A2 and 2',5'A3 had virtually no effect. The reduction in infe...
Article
The kinetic and structural properties of purified, homogeneous pyruvate kinase type M2 from chicken lung and tumors, including that from Rous sarcoma virus-transformed chicken fibroblasts, have been compared. The "tumor enzyme" is characterized by a low affinity for phosphoenolpyruvate, pronounced serine activation, and strong alanine inhibition as...
Article
A rapid and convenient assay for the expression of endogenous retrovirus glycoprotein in adult chickens has been developed based on the enzyme-linked immunosorbent assay (ELISA) principle. This method has been standardized using the conventional chick helper factor test. In the course of establishing this method with a large number of specific path...
Article
Responsiveness to extracellular signals may participate in the control of cell division. This hypothesis was examined by comparing the adenosine responsiveness of Rous sarcoma virus (RSV)-transformed cells and untransformed cells. The results show that RSV-transformed chicken embryo cells (CEC) are more responsive to adenosine than Rous associated...
Article
Rous sarcoma virus (RSV)-infected chicken embryo cells were used to study the effect of viral transformation on the hormone-stimulated synthesis of cyclic AMP. Transformation by RSV greatly increased the cells' ability to synthesize and accumulate cyclic AMP in response to the beta-adrenergic agonist isoproterenol as compared to untransformed cells...
Article
We have studied the processing of the RSV glycoprotein precursor gPr92env to mature viral disulfide-linked gp85 and gp35 (VGP). The first aspect concerned the steps involved in the processing event. We could show that, in addition to proteolytic cleavage, the processing of gPr92env involves the conversion of oligosaccharides from the high-mannose t...
Article
The half-life of metabolically labeled pp60src of the Prague A strain of Rous sarcoma virus and of several transformation-defective, temperature-sensitive mutants was investigated by pulse-labeling infected cells with [35S]methionine, chasing for different times, and immunoprecipitating pp60src with tumor-bearing rabbit serum. These experiments sho...
Article
The half-life of metabolically labeled pp60src of the Prague A strain of Rous sarcoma virus and of several transformation-defective, temperature-sensitive mutants was investigated by pulse-labeling infected cells with [35S]methionine, chasing for different times, and immunoprecipitating pp60src with tumor-bearing rabbit serum. These experiments sho...
Article
A cellular protein of apparent Mr 34,000--36,000 was suggested as a possible physiological substrate for the protein kinase (EC 2.7.1.37) activity associated with the transforming gene product of Rous sarcoma virus. We find this protein to migrate with an apparent Mr of 38,000 in NaDodSO4/polyacrylamide gels. It was not separable from cytosolic mal...
Chapter
Tumor cells differ from their normal counterparts in two important functional properties: they are capable of indefinite proliferation and they display a more or less drastically altered metabolism. The fundamental molecular mechanisms responsible for these dramatic pheno-typic changes are not yet understood, but can be directly investigated by the...
Article
ST 529 is a temperature-sensitive mutant of Rous sarcoma virus (RSV) strain SR-A, which causes an unusual pattern of phenotypic changes in cells that it transforms. At 35°, ST 529-transformed cells exhibit an elongated, fusiform morphology (morphf), and also possess an aberrant and “unlinked” phenotypic pattern of transformation-related properties....
Article
During the onset of transformation, Rous sarcoma virus-infected cells undergo characteristic morphological changes that reflect the biochemical events induced by the viral src gene. Temperature downshift experiments using chick embryo cells infected with transformation-defective temperature-sensitive viral mutants have shown two major morphological...
Article
The pp60src kinase activity of cells infected with temperature-conditional mutants of Rous sarcoma virus (RSV), which induce only a partial transformation, was compared to the pattern of transformation parameters induced by these mutants. The tsGI251-infected cells were thermosensitive for hexose transport, fibrinolysis, morphological alterations a...
Article
Fifteen transformation defective sensitive mutants of Rous sarcoma virus have been investigated to see if the expression of the pp60src-associated protein kinase activity correlated with other parameters of transformation such as altered growth control, morphological changes, increased hexose transport, and increased plasminogen activator protease...