Showing papers on "Signal transduction published in 1986"

Studies and perspectives of protein kinase C

Abstract: Protein kinase C, an enzyme that is activated by the receptor-mediated hydrolysis of inositol phospholipids, relays information in the form of a variety of extracellular signals across the membrane to regulate many Ca2+-dependent processes. At an early phase of cellular responses, the enzyme appears to have a dual effect, providing positive forward as well as negative feedback controls over various steps of its own and other signaling pathways, such as the receptors that are coupled to inositol phospholipid hydrolysis and those of some growth factors. In biological systems, a positive signal is frequently followed by immediate negative feedback regulation. Such a novel role of this protein kinase system seems to give a logical basis for clarifying the biochemical mechanism of signal transduction, and to add a new dimension essential to our understanding of cell-to-cell communication.

Activation of two signal-transduction systems in hepatocytes by glucagon

Abstract: The ability of glucagon to stimulate glycogen breakdown in liver played a key part in the classic identification of cyclic AMP and hormonally stimulated adenylate cyclase1. But several observations indicate that glucagon can exert effects independent of elevating intracellular cAMP concentrations2–7. These effects are probably mediated by an elevation8,9 of the intracellular concentration of free Ca2+ although the mechanism by which this occurs is unknown. We show here that glucagon, at the low concentrations found physiologically, causes both a breakdown of inositol phospholipids and the production of inositol phosphates. Indeed, we show that the glucagon analogue, (1-N-α-trinitrophenylhistidine,12-homo-arginine)glucagon (TH-glucagon), which does not activate adenylate cyclase or cause any increase in cAMP in hepatocytes yet can fully stimulate glycogenolysis, gluconeogenesis and urea synthesis10, stimulates the production of inositol phosphates. This stimulation of inositol phospholipid metabolism by low concentrations of glucagon provides a mechanism11,12 whereby glucagon can exert cAMP-independent actions on target cells. We suggest that hepatocytes possess two distinct receptors for glucagon, a GR-1 receptor coupled to stimulate inositol phospholipid breakdown and a GR-2 receptor coupled to stimulate adenylate cyclase activity.

Structural heterogeneity and functional domains of murine immunoglobulin G Fc receptors

Abstract: Binding of antibodies to effector cells by way of receptors to their constant regions (Fc receptors) is central to the pathway that leads to clearance of antigens by the immune system The structure and function of this important class of receptors on immune cells is addressed through the molecular characterization of Fc receptors (FcR) specific for the murine immunoglobulin G isotype Structural diversity is encoded by two genes that by alternative splicing result in expression of molecules with highly conserved extracellular domains and different transmembrane and intracytoplasmic domains The proteins encoded by these genes are members of the immunoglobulin supergene family, most homologous to the major histocompatibility complex molecule E beta Functional reconstitution of ligand binding by transfection of individual FcR genes demonstrates that the requirements for ligand binding are encoded in a single gene These studies demonstrate the molecular basis for the functional heterogeneity of FcR's, accounting for the possible transduction of different signals in response to a single ligand

The World of the Cell

Abstract: 1. A Preview of the Cell 2. The Chemistry of the Cell 3. The Macromolecules of the Cell 4. Cells and Organelles 5. Bioenergetics: The Flow of Energy in the Cell 6. Enzymes: The Catalysts of Life 7. Membranes: Their Structure, Function, and Chemistry 8. Transport Across Membranes: Overcoming the Permeability Barrier 9. Chemotrophic Energy Metabolism: Glycolysis and Fermentation 10. Chemotrophic Energy Metabolism: Aerobic Respiration 11. Phototrophic Energy Metabolism: Photosynthesis 12. The Endomembrane System and Peroxisomes 13. Signal Transduction Mechanisms: I. Electrical and Synaptic Signaling in Neurons 14. Signal Transduction Mechanisms: II. Messengers and Receptors 15. Cytoskeletal Systems 16. Cellular Movement: Motility and Contractility 17. Beyond the Cell: Cell Adhesion, Cell Junctions, and Extracellular Structures 18. The Structural Basis of Cellular Information: DNA, Chromosomes, and the Nucleus 19. The Cell Cycle, DNA Replication, and Mitosis 20. Sexual Reproduction, Meiosis, and Genetic Recombination 21. Gene Expression: I. The Genetic Code and Transcription 22. Gene Expression: II. Protein Synthesis and Sorting 23. The Regulation of Gene Expression 24. Cancer Cells Appendix Principles and Techniques of Microscopy Glossary Photo, Illustration, and Text Credits Index

The role of phosphoinositides in signal transduction.

Abstract: The binding of agonists to protein receptors at the cell surface is well established, but the mechanism by which the \"message\" generated at the receptor is transferred to the inside of the cell is not clearly understood for all types of stimuli. One class of receptors mediates its response through formation of cAMP, catalyzed by adenylate cyclase (a protein present on the cytoplasmic side of the membrane). The coupling of adenylate cyclase to the receptor is further regulated by GTP-binding proteins [186, 258]. It has been suggested that conversion of phosphatidylethanolamine to phosphatidylcholine plays a role in the coupling of receptors to adenylate cyclase [120], although evidence against this hypothesis has also been presented [216; see 202]. Another class of receptors mediates its response through Ca :+ mobilization. Evidence is rapidly mounting that a specific class of phosphotipids, i.e., the phosphoinositides, plays an important role in signal transduction from the receptors at the plasma membrane. There have been numerous recent reviews on the various aspects of phosphoinositide metabolism and its role in signal transduction [see 1, 3, 23, 25, 71, 81, 82, 88, 89, 118, I19, 125, 148, 197,207,211, 220, 237,239]. The emphasis of this review will be to analyze the recent developments ~ and how they relate to earlier observations.

Nerve growth factor rapidly induces c-fos mRNA in PC12 rat pheochromocytoma cells.

Abstract: The nerve growth factor (NGF)-mediated increase in c-fos gene expression in the rat pheochromocytoma PC12 cell line has been investigated. NGF treatment of PC12 cells results in an increased level of c-fos mRNA within 15 min. An approximately 100-fold increase in the level of c-fos mRNA occurs 30-45 min after exposure to NGF and the c-fos mRNA concentration returns to its basal level 2 hr after NGF treatment. Thus, the half-life of this RNA transcript is extremely short. In the presence of cycloheximide, the c-fos gene is superinduced and the increased level of c-fos mRNA persists for at least 24 hr. The induction of c-fos gene expression was further studied by utilizing a monoclonal antibody (mAb-192) that is directed against the NGF receptor but does not compete with NGF for binding to the receptor. Treatment of the cells with mAb-192 inhibits the NGF-stimulated elevation of c-fos mRNA, suggesting that the antibody may interfere with the receptor's ability to generate the signal required to stimulate the transcription of this gene. NGF is not the only agent capable of inducing c-fos gene expression in these cells; epidermal growth factor, the tumor promoter phorbol 12-myristate 13-acetate, and the calcium ionophore A23187, agents that induce the c-fos gene in other cell lines, are also effective in PC12 cells. The mRNA for the nuclear protein fos is rapidly induced by NGF and other agents to which PC12 cells respond. This supports the hypothesis that the fos gene product may play a role in signal transduction.

Cholera toxin inhibits the T-cell antigen receptor-mediated increases in inositol trisphosphate and cytoplasmic free calcium.

Abstract: The addition of monoclonal antibodies to the antigen receptor complex on the malignant human T-cell line Jurkat generates increases in inositol trisphosphate and in the concentration of cytoplasmic free calcium. Exposure of Jurkat cells to cholera toxin for 3 hr inhibited these receptor-mediated events and led to a selective, partial loss of the antigen receptor complex from the cellular surface. None of the effects of cholera toxin on the antigen receptor complex were mimicked by the B subunit of cholera toxin or by increasing intracellular cAMP levels with either forskolin or 8-bromo cAMP. These results suggest that a cholera toxin substrate can regulate signal transduction by the T-cell antigen receptor.

Thy-1 functions as a signal transduction molecule in T lymphocytes and transfected B lymphocytes.

Abstract: Thy-1, a glycoprotein of relative molecular mass 25,000 (25K), is a major constituent of the cell surface of mouse thymocytes, peripheral T cells and neurones1. In man, Thy-1 is present on neurones and on a small percentage of thymocytes, but is absent from peripheral T cells2. The amino-acid3,4 and complementary DNA5–7 sequences of Thy-1 indicate that it has a structure similar to an isolated V (variable region) domain of immunoglobulin4. Although the function of Thy-1 is unknown, the ability of different anti-Thy-1 monoclonal antibodies to activate murine T cells8,9 or induce functional changes in neuronal cells in vitro10 suggests that Thy-1 is involved in transmembrane signalling. We now show that crosslinking of murine Thy-1 triggers a rapid rise in the cytoplas-mic free calcium concentration ([Ca2+]i), not only in murine T cells and Thy-1.2-transfected human T cells, but also in murine B-lymphoma cells transfected with the murine thy-1.2 gene. These results indicate that the generation and transduction of the signal leading to the rise in [Ca2+]i is independent of the T-cell receptor and other T-cell-spec i fie molecules. The preservation of the [Ca2+]i-modulating function of Thy-1 in various lymphoid cells of two species further suggests that the necessary signal either originates in the Thy-1 molecule itself or is generated in concert with a highly conserved molecules(s) associated with Thy-1.

Superoxide anion release by human endothelial cells: Synergism between a phorbol ester and a calcium ionophore

Abstract: In order to study the signal transduction mechanism of human endothelial cells (EC), the regulation of superoxide anion (O2−) release in EC has been investigated using the calcium ionophore A23187 and phorbol myristate acetate (PMA), a potential activator of the Ca2+ activated, phospholipid-dependent protein kinase, designated “protein kinase C.” PMA enhanced O2− release from EC, and this enhancement occurred regardless of the presence or absence of extracellular Ca2+. A similar increase was produced by A23187; omission of extracellular Ca2+ prevented this increase. Simultaneous stimulation with PMA and A23187 produced a large increase in O2− release at submaximal concentrations of these agents, which, when added separately, caused minimal effects. These findings indicate that the activation of protein kinase C and mobilization of Ca2+ evoked by PMA and A23187 respectively are synergistically effective for eliciting a full physiological response of EC in the generation and release of O2−.

Pertussis toxin-sensitive pathway in the stimulation of c-myc expression and DNA synthesis by bombesin

Abstract: The bombesin-like peptides are potent mitogens for Swiss 3T3 fibroblasts, human bronchial epithelial cells, and cells isolated from small cell carcinoma of the lung. The mechanism of signal transduction in the proliferative response to bombesin was investigated by studying the effect of Bordetella pertussis toxin on bombesin-stimulated mitogenesis. At nanomolar concentrations, bombesin increased levels of c-myc messenger RNA and stimulated DNA synthesis in Swiss 3T3 cells. Treatment of the cells with pertussis toxin (5 nanograms per milliliter) completely blocked bombesin-enhanced c-myc expression and eliminated bombesin-stimulated DNA synthesis. This treatment had essentially no effect on the mitogenic responses to either platelet-derived growth factor or phorbol 12,13-dibutyrate. These results suggest that the mitogenic actions of bombesin-like growth factors are mediated through a pertussis toxin-sensitive guanine nucleotide-binding protein. Furthermore they indicate that bombesin-like growth factors act through pathways that are different from those activated by platelet-derived growth factor.

Antibodies reactive with the B1 molecule inhibit cell cycle progression but not activation of human B lymphocytes.

Abstract: The B1 cell surface molecule (CD20) is a 35-kDa phosphoprotein expressed by B lineage cells during most stages of differentiation. Some monoclonal antibodies reactive with B1 induce activation while others, anti-B1a, inhibit B lymphocyte function. To further determine the requirement of B1 molecule function in proliferation and differentiation the effects of anti-B1a antibody binding on early cellular activation events were examined. Immunoglobulin secretion of lymphocyte cultures stimulated with pokeweed mitogen was maximally inhibited if the antibody (1-10 micrograms/ml) was added during the first 24 h of culture. However, even high antibody concentrations were unable to inhibit increases in free intracellular Ca2+ concentrations immediately following cross-linkage of cell surface immunoglobulin, or inhibit cell enlargement and the expression of transferrin and interleukin 2 receptors. Antibody binding to B1 inhibited RNA synthesis (37-80%) and progression through cell cycle following activation. In contrast, proliferation induced by phorbol myristate acetate was not inhibited by antibody binding to the B1 molecule. The findings that the earliest activation events and phorbol myristate acetate-induced proliferation were not inhibited by antibody binding to B1 suggest that inhibition is due to the blocking of a step of the activation process required for cell cycle progression and differentiation, rather than blocking initial signal transduction across the membrane or providing a negative or suppressive signal.

Translocation of protein kinase C during membrane immunoglobulin-mediated transmembrane signaling in B lymphocytes.

Abstract: Previous studies have implicated a role for protein kinase C (PKC) in transmembrane signal transduction by B cell surface immunoglobulin (Ig). Specifically, the pharmacologic PKC activator phorbol myristate acetate mimics the biologic effects of mIg cross-linking ligands, and cross-linking of membrane Ig (mIg) induces polyphosphoinositide hydrolysis generating diacylglycerol, a potent activator of PKC. Studies described here additionally implicate PKC in mIg-mediated signaling by demonstrating rapid translocation of activatable PKC (PKCa) from cytosol to Triton-soluble membrane fractions after cross-linking of cell surface IgM or IgD. This response, which is also induced by phorbol myristate acetate and lipolysaccharide, is detectable within 1 min of mIg cross-linking and is followed within 4 min by additional translocation of PKCa to a Triton-insoluble particulate compartment. The ability of dbcAMP plus theophylline to inhibit polyphosphoinositide hydrolysis, PKCa translocation, and the B cell's subsequent biological response suggests that these events may be causally related.

Signal transduction in insulin secretion: comparison between fuel stimuli and receptor agonists.

Abstract: The initial events in signal transduction in insulin-secreting cells are summarized in FIGURE 8. Both nutrient stimuli, such as glucose and amino acids and the muscarinic agonist carbachol (carbamylcholine) raise [Ca2+]i. Although the rise in [Ca2+]i precedes the stimulation of insulin release, it is not a moment-to-moment regulator of release. The metabolizable fuel stimuli cause Ca2+ influx through voltage-dependent Ca2+ channels following depolarization of the membrane potential. In contrast, carbachol, which does not depolarize, elicits Ptd Ins 4,5-P2 hydrolysis, a reaction catalyzed by phospholipase C. The generation of Ins 1,4,5-P3 in this instance is Ca2+ independent, but appears to involve a GTP-binding protein. However, this protein is not a substrate for pertussis toxin. The levels of Ins 1,4,5-P3, which releases Ca2+ from an ATP-dependent Ca2+ pool of the endoplasmic reticulum, are increased prior to the rise in [Ca2+]i. The mitochondria may take up Ca2+ after large increases in [Ca2+]i. A previously proposed second messenger, arachidonic acid, is much less selective than Ins 1,4,5-P3 in that it releases Ca2+ from mitochondria as well as from the endoplasmic reticulum in a slow and irreversible manner. As Ins 1,4,5-P3 is also generated during glucose stimulation of islets, albeit in a Ca2+-dependent manner, this metabolite could mediate not only the action of carbachol but also contribute to amplifying the [Ca2+]i rise in response to glucose.

Pertussis toxin or phorbol 12-myristate 13-acetate can distinguish between epidermal growth factor- and angiotensin-stimulated signals in hepatocytes.

Abstract: Epidermal growth factor (EGF) causes rapid increases in free intracellular Ca2+ and stimulates the phosphorylation of 11 cytosolic proteins in hepatocytes. Ten of the 11 cytosolic proteins altered by EGF are identical to those affected by angiotensin II, a hormone that stimulates the breakdown of phosphatidylinositol 4,5-bisphosphate. An increase in the phosphorylation of the other protein, spot c (Mr = 36,000, pI = 5.5), is observed only with EGF. Treatment of intact rats with pertussis toxin to ADP-ribosylate Ni, the inhibitory GTP-binding protein of the adenylate cyclase complex, abolished the effect of EGF on Ca2+ mobilization and on the phosphorylation of the 10 proteins affected in common with angiotensin II. This treatment had minimal effects on the ability of EGF to stimulate the phosphorylation of its unique substrate, spot c. In marked contrast, modification of Ni did not block the ability of angiotensin II to stimulate Ca2+ mobilization or protein phosphorylation. Pretreatment of normal hepatocytes with 4 beta-phorbol 12-myristate 13-acetate blocked all responses to EGF, including the increased phosphorylation of spot c, but had no effect on the responses to angiotensin II. These results imply that Ni or a similar pertussis toxin substrate may mediate the apparent effects of EGF on phosphatidylinositol breakdown and that protein kinase C may regulate a site in the transduction pathway. Angiotensin II appears to use a different signal transduction mechanism to stimulate phosphatidylinositol metabolism in hepatocytes.

Immunodeficiency of aging: restorative effects of phorbol ester combined with calcium ionophore

Abstract: Current models for lectin-induced T cell proliferation suggest that activation of protein kinase C (PK-C) and elevation of cytoplasmic Ca2+ may both play important roles in the earliest phases of signal transduction. To learn more about the relative inability of T cells from old mice to proliferate in response to mitogenic stimuli, we attempted to stimulate T cells by the synergistic effects of a PK-C activator, phorbol myristate acetate (PMA), and the calcium ionophore ionomycin. T cells from young mice respond as well to optimal combinations of these agents as they do to the strong polyclonal activator Con A, but T cells from old mice respond much better to PMA plus ionomycin than they do to Con A. This result suggests that an inability to transduce the signal supplied by extracellular ligands into the intracellular signals represented by Ca2+ and PK-C activators may underlie the age-associated loss of T cell reactivity. We also found evidence for a second defect in old T cells related to their response to elevated intracellular Ca2+: old T cells, compared with young, required higher levels of ionomycin for maximal proliferation.

Dual regulation of adenylate cyclase. A signal transduction mechanism of membrane receptors.

Abstract: The hormone-sensitive adenylate cyclase is a multi-component system embedded in the lipid bilayer of the plasma membrane and serves as a signal transduction system for various membrane receptors. The complete system consists of various receptor molecules, which sensitize the external ligands, the effector enzyme adenylate cyclase, which catalyzes the formation of cyclic AMP from ATP, and two guanine nucleotide-binding regulatory proteins (N or G proteins), which transduce the signals from the receptors to the adenylate cyclase. Depending on the receptor type activated by a ligand, stimulatory or inhibitory, either the stimulatory or the inhibitory N protein is activated and induces stimulation or inhibition of adenylate cyclase with subsequent increase or decrease in cellular cyclic AMP levels. In this paper, the mechanisms of this hormonal signal transduction system and its regulation will briefly reviewed, with some emphasis on the cardiac system.

Inositol lipid metabolism and signal transduction in clonal pituitary cells.

Abstract: A number of clonal cell lines derived from a rat pituitary tumour, collectively termed GH cells, have retained a range of differentiated cell functions, including their ability to secrete the hormones prolactin and growth hormone in response to stimuli such as thyrotropin-releasing hormone (TRH). The mechanisms underlying this release process involve, at least in part, an increase in cytosolic free calcium levels, and the cells have proved useful as a model system in studies of receptor-controlled calcium mobilization. The initial response of the cells to the addition of TRH now appears to be the interaction of the occupied TRH receptor with a GTP-binding protein. A sophisticated signalling system is then activated which initially involves the phosphodiesteratic hydrolysis of phosphatidylinositol 4,5-bisphosphate to 1,2-diacylglycerol and inositol 1,4,5-trisphosphate. Both of these products are important intracellular messengers, and their formation leads to a plethora of biochemical and electrical changes which culminate in the biphasic release of hormone from the cell. The changes in cytosolic free calcium that occur following TRH addition follow a complex temporal pattern. Within 1 s, the concentration starts to increase from a resting level, in the range 100–150 nmol l-1, to a peak value of around 1 mumol l-1 which is attained within 6–8 s. This ‘spike’ of calcium is almost exclusively derived from intracellular stores, probably the endoplasmic reticulum, in response to the formation of inositol 1,4,5-trisphosphate. With high concentrations of the peptide, the cytosolic free calcium concentration declines promptly, due to the activation of a protein kinase C-mediated extrusion and/or sequestration process. This inhibitory phase is less marked at low agonist concentrations but, in all cases, is superseded by a second increase in free calcium, which is due to the stimulated influx of the cation through dihydropyridine-sensitive calcium channels. These biphasic changes in calcium, in concert with the activation of protein kinase C, appear sufficient to regulate prolactin secretion.

Ligand-Receptor Dynamics and Signal Amplification in the Neutrophil

Abstract: Publisher Summary This chapter describes the pathways that regulate cell activation at molecular level and elaborates a conceptual framework to account for the sensitivity of cell function to the conditions of stimulation. The perspective is quantitative to the extent that the stoichiometry, amplification, and duration of receptor activation and signal generation are considered. This approach relies on a significant extent upon dynamic and kinetic measurements. In the chapter, preliminary data in the activation sequence has been employed and the quantitative relationships among the activation events are speculated. Quantitative studies of ligand–receptor interactions have been accomplished most successfully with high-affinity monovalent ligands that can be appropriately labeled. The potential signaling events in cell activation may be roughly divided into those that are generated inside the cell in response to transmembrane transduction or species that are permitted entry into the cell following transduction. There is a remarkable ferment in the molecular understanding of signal transduction in many cell types. In the neutrophil, information has become available that is beginning to permit an analysis of the most intimate details of amplification and termination of the biochemical pathways which lead to cell activation. The neutrophil is a remarkable cell type, exhibiting diverse and fascinating functions, distinct receptors for many classes of stimulatory molecules, and sensitivity to the conditions of stimulus application. The chapter attempts to provide a conceptual and quantitative outlook upon future developments that encompass biochemical, biophysical, and physiological investigations.

Oncogenes And Growth Control

Abstract: I Growth Factors and Proto-Oncogenes in Development and Differentiation.- The Expression of Growth Factors and Growth Factor Receptors During Mouse Embryogenesis.- A Role for Proto-Oncogenes in Differentiation?.- Tissue-Specific Expression and Possible Functions of pp60c-src.- II Growth Factors, Receptors, and Related Oncogenes.- The Granulocyte-Macrophage Colony-Stimulating Factors.- Role of PDGF-Like Growth Factors in Autocrine Stimulation of Growth of Normal and Transformed Cells.- Transforming Growth Factor-?.- Transforming Growth Factor-?.- The Physiology of Epidermal Growth Factor.- Structural Relationships Between Growth Factor Precursors and Cell Surface Receptors.- Regulation of Cell Growth by the EGF Receptor.- Mutational Analysis of v-erbB Oncogene Function.- The c-fms Proto-Oncogene and the CSF-1 Receptor.- Activation of the c-src Gene.- Normal and Transforming N-Terminal Variants of c-abl.- Transformation by the v-abl Oncogene.- mos.- Structure and Function of the Human Interleukin-2 Receptor.- III Signal Transduction and ras Oncogenes.- Phosphorylation in Signal Transmission and Transformation.- Inositol Lipids and Cell Proliferation.- Protein Kinase C.- The Relevance of Protein Kinase C Activation, Glucose Transport, and ATP Generation in the Response of Haemopoietic Cells to Growth Factors.- Cytoplasmic pH and Free Ca2+ in the Action of Growth Factors.- Epidermal Growth-Factor Mediation of S6 Phosphorylation During the Mitogenic Response: A Novel S6 Kinase.- Role of G Proteins in Transmembrane Signaling: Possible Functional Homology with the ras Proteins.- The ras Gene Family.- RAS Genes and Growth Control in the Yeast Saccharomyces cerevisiae.- IV Gene Expression and Nuclear Oncogenes.- Regulation of Human Globin Gene Expression.- Regulation of Gene Expression by Steroid Hormones.- Enhancers as Control Elements for Tissue-Specific Transcription.- The Effect of DNA Methylation on DNA-Protein Interactions and on the Regulation of Gene Expression.- Trans-Acting Elements Encoded in Immediate Early Genes of DNA Tumor Viruses.- Transactivator Genes of HTLV-I, II, and III.- Involvement of Proto-Oncogenes in Growth Control: The Induction of c-fos and c-myc by Growth Factors.- Oncogenes and Interferons: Genetic Targets for Animal Cell Growth Factors.- Regulation of c-myc Expression in Normal and Transformed Mammalian Cells.- Properties of the myc and myb Gene Products.- The fos Oncogene and Transformation.- p53: Molecular Properties and Biological Activities.- V Malignant Transformation as a Multistep Process.- Oncogene Cooperativity in Stepwise Transformation of Rodent Embryo Fibroblasts by Polyoma Virus.- Role of the Middle T: pp60c-src Complex in Cellular Transformation by Polyoma Virus.- Oncogenes Cooperate, but How?.- Individual and Combined Effects of Viral Oncogenes in Hematopoietic Cells.- Multiple Factors Involved in B-Cell Tumorigenesis.- Molecular Events Associated with Tumor Initiation, Promotion, and Progression in Mouse Skin.- Amplification of Proto-Oncogenes and Tumor Progression.- Suppression of the Neoplastic Phenotype.- VI Oncogenesis in Transgenic Mice.- Oncogenesis in Transgenic Mice.

BSF1 induces membrane protein phosphorylation but not phosphoinositide metabolism, Ca2+ mobilization, protein kinase C translocation, or membrane depolarization in resting murine B lymphocytes.

Abstract: The findings presented in this study provide evidence that BSF1 receptors and mIg transmit signals via dissimilar transduction mechanisms that result in a common biologic response, hyper-Ia expression. Specifically, BSF1-containing supernatant does not induce PtdInsP2 hydrolysis as determined by measurement of PtdOH and InsP3. Additionally, BSF1 does not stimulate Ca2+ mobilization, PKC translocation from cytosol to membrane, or membrane depolarization. All of these metabolic events appear to play a central role in hyper-Ia expression mediated by mIg and are initiated after treatment of resting B cells with anti-Ig antibodies. In vitro phosphorylation studies with partially purified plasma membranes from resting B cells revealed that BSF1 interaction with membrane receptors stimulates a membrane-associated protein kinase that phosphorylates an endogenous protein of 44 KDa. Anti-Ig does not stimulate phosphorylation of the 44 KDa protein, suggesting that it does not activate the membrane-associated protein kinase. This observation provides the first evidence of a signal transduction mechanism associated with BSF1-receptor ligation. It indicates that although BSF1 does not modulate events associated with PKC activation, it may function via activation of a membrane-associated protein kinase. This provides a focal point for further studies directed at elucidating signal transduction resulting from BSF1-receptor interaction.

The serotonin‐S2 Receptor: A receptor‐transducer coupling model to explain insurmountable antagonist effects

Abstract: Five serotonin-S2 antagonists, ketanserin, pipamperone, methysergide, ritanserin, and LSD, were tested for their ability to inhibit signal transduction coupled to the serotonin-S2 receptor by measuring the serotonin-induced [32P] phosphatidic acid formation. The five drugs inhibited the response in a non-competitive manner. Since drugs such as ketanserin and pipamperone were found to dissociate rapidly from serotonin-S2 receptor sites in binding studies, slowly reversible binding can hardly explain the apparent non-competitive inhibition of the biochemical effect. The authors, therefore, propose a new model of interaction between the serotonin-S2 receptor macromolecule and the signal transducing system that is compatible with the present and previous experimental observations.