Showing papers on "Receptor expression published in 2003"

The emerging role of lysophosphatidic acid in cancer.

Abstract: The bioactive phospholipid lysophosphatidic acid (LPA) stimulates cell proliferation, migration and survival by acting on its cognate G-protein-coupled receptors. Aberrant LPA production, receptor expression and signalling probably contribute to cancer initiation, progression and metastasis. The recent identification of ecto-enzymes that mediate the production and degradation of LPA, as well as the development of receptor-selective analogues, indicate mechanisms by which LPA production or action could be modulated for cancer therapy.

A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans

Abstract: How left/right functional asymmetry is layered on top of an anatomically symmetrical nervous system is poorly understood. In the nematode Caenorhabditis elegans, two morphologically bilateral taste receptor neurons, ASE left (ASEL) and ASE right (ASER), display a left/right asymmetrical expression pattern of putative chemoreceptor genes that correlates with a diversification of chemosensory specificities. Here we show that a previously undefined microRNA termed lsy-6 controls this neuronal left/right asymmetry of chemosensory receptor expression. lsy-6 mutants that we retrieved from a genetic screen for defects in neuronal left/right asymmetry display a loss of the ASEL-specific chemoreceptor expression profile with a concomitant gain of the ASER-specific profile. A lsy-6 reporter gene construct is expressed in less than ten neurons including ASEL, but not ASER. lsy-6 exerts its effects on ASEL through repression of cog-1, an Nkx-type homeobox gene, which contains a lsy-6 complementary site in its 3' untranslated region and that has been shown to control ASE-specific chemoreceptor expression profiles. lsy-6 is the first microRNA to our knowledge with a role in neuronal patterning, providing new insights into left/right axis formation.

Cultured astrocytes express toll‐like receptors for bacterial products

Abstract: It has become apparent that astrocytes may be important contributors to inflammatory immune responses within the brain in response to microbial challenges. To date, the mechanisms that underlie activation of this major glial cell type by such challenges have not been investigated. In the present study, we present evidence for members of a recently discovered family of receptors for highly conserved microbial components, the Toll-like receptors (TLRs), in isolated cultures of primary murine astrocytes. We describe the low-level constitutive expression of messenger RNA-encoding TLR2, TLR4, TLR5, and TLR9 in resting cultures of these cells. Importantly, the level of expression of messenger RNA for each of these receptors is markedly elevated following exposure to specific bacteria-derived ligands for these receptors. The functional expression of these receptor proteins is further supported by the ability of known ligands for each TLR to induce both message expression and protein secretion of the proinflammatory cytokine, interleukin-6. In addition, the recent availability of antibodies to TLR2 and TLR4 has enabled us to demonstrate directly the presence of these receptors on astrocytes by Western blot and immunofluorescence analysis, respectively. Furthermore, we have confirmed the sensitivity of such receptor expression to ligand stimulation. The present demonstration of Toll-like microbial pattern-recognition receptors on primary astrocytes provides a mechanistic link between bacterial challenge and inflammatory immune responses that may be an important component of the pathologies of bacterially induced inflammatory CNS disorders.

Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling.

Abstract: A new paradigm for asthma pathogenesis is presented in which exaggerated inflammation and remodeling in the airways are a consequence of abnormal injury and repair responses arising from a subject's susceptibility to components of the inhaled environment. An epithelial-mesenchymal trophic unit becomes activated to drive pathologic remodeling and smooth muscle proliferation through complex cytokine interactions. Histamine, prostanoids, and cysteinyl leukotrienes (CysLTs) are potent contractile agonists of airway smooth muscle (ASM). The CysLTs appear to play a central role in regulating human ASM motor tone and phenotypic alterations, manifested as hypertrophy and hyperplasia in chronic severe asthma. The CysLTs augment growth factor–induced ASM mitogenesis through activation of CysLT receptors. Although they mediate their contractile effects by increasing phosphoinositide turnover and inducing increased cytosolic calcium, new data suggest that part of the contractile effect may be independent of calcium mobilization. Prostaglandin E 2 , the predominant eicosanoid product of the airway epithelium, is a potent inhibitor of mitogenesis, collagen synthesis, and mesenchymal cell chemotaxis and therefore can suppress inflammation and fibroblast activation. The capacity of the epithelium for CysLT synthesis is inversely related to its ability to make PGE 2 . The ASM is capable of expressing both leukotriene-synthesizing enzymes and CysLT receptors, and cytokines upregulate the receptor expression. This may be an explanation for the CysLTs promoting airway hyperresponsiveness in asthma. The CysLTs play an important role in the airway remodeling seen in persistent asthma that includes increases of airway goblet cells, mucus, blood vessels, smooth muscle, myofibroblasts, and airway fibrosis. Evidence from a mouse model of asthma demonstrated that CysLT 1 receptor antagonists inhibit the airway remodeling processes, including eosinophil trafficking to the lungs, eosinophil degranulation, T H 2 cytokine release, mucus gland hyperplasia, mucus hypersecretion, smooth muscle cell hyperplasia, collagen deposition, and lung fibrosis. (J Allergy Clin Immunol 2003;111:S18-36.)

The epidermal growth factor receptor mediates radioresistance.

Abstract: Purpose The epidermal growth factor (EGF) receptor is frequently overexpressed in malignant tumors, and its level is correlated with increased cellular resistance to ionizing radiation. However, no precedent studies have investigated whether expression of EGF receptor would by itself confer on cancer cells resistance to radiation. The current study is aimed to address this question. Methods and materials A full-length human EGF receptor expression vector was transfected into the OCA-I murine ovarian carcinoma cells for stable clones expressing various levels of EGF receptors. Apoptosis and cell clonogenic survival assays were used to evaluate the sensitivity of the resulting cell clones to ionizing radiation. Results OCA-I cell clones expressing various levels of EGF receptor (OCA-I EGFR) were obtained. These clones showed an EGF receptor level–dependent increase in resistance to ionizing radiation, measured by apoptosis and cell clonogenic survival assays. Compared with the results for parental OCA-I and control vector-transfected OCA-I cells at the 10% cell survival level, the radioresistance was increased by a factor of 1.60 for EGFR-C5 (high level of EGF receptor expression), 1.37 for EGFR-C3 (intermediate level of EGF receptor expression), and 1.28 for EGFR-C1 (low level of EGF receptor expression). Treatment of the OCA-I EGF receptor transfectants with the anti-EGF receptor monoclonal antibody C225 downregulated the levels of EGF receptor, reduced the phosphorylation levels of EGF receptor downstream substrates (such as Akt and MAPK), and reversed the cellular radioresistance. Conclusion Our results demonstrate that overexpression of the EGF receptor conferred cellular resistance to ionizing radiation. The EGF receptor is thus a valid target for potential radiosensitization.

The entry of entry inhibitors: A fusion of science and medicine

Abstract: For HIV-1 to enter a cell, its envelope protein (Env) must sequentially engage CD4 and a chemokine coreceptor, triggering conformational changes in Env that ultimately lead to fusion between the viral and host cell membranes. Each step of the virus entry pathway is a potential target for novel antiviral agents termed entry inhibitors. A growing number of entry inhibitors are under clinical development, with one having already been licensed by the Food and Drug Administration. With the emergence of virus strains that are largely resistant to existing reverse transcriptase and protease inhibitors, the development of entry inhibitors comes at an opportune time. Nonetheless, because all entry inhibitors target in some manner the highly variable Env protein of HIV-1, there are likely to be challenges in their efficient application that are unique to this class of drugs. Env density, receptor expression levels, and differences in affinity and receptor presentation are all factors that could influence the clinical response to this promising class of new antiviral agents.

Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. Discussion

Abstract: A new paradigm for asthma pathogenesis is presented in which exaggerated inflammation and remodeling in the airways are a consequence of abnormal injury and repair responses arising from a subject's susceptibility to components of the inhaled environment. An epithelial-mesenchymal trophic unit becomes activated to drive pathologic remodeling and smooth muscle proliferation through complex cytokine interactions. Histamine, prostanoids, and cysteinyl leukotrienes (CysLTs) are potent contractile agonists of airway smooth muscle (ASM). The CysLTs appear to play a central role in regulating human ASM motor tone and phenotypic alterations, manifested as hypertrophy and hyperplasia in chronic severe asthma. The CysLTs augment growth factor-induced ASM mitogenesis through activation of CysLT receptors. Although they mediate their contractile effects by increasing phosphoinositide turnover and inducing increased cytosolic calcium, new data suggest that part of the contractile effect may be independent of calcium mobilization. Prostaglandin E 2 , the predominant eicosanoid product of the airway epithelium, is a potent inhibitor of mitogenesis, collagen synthesis, and mesenchymal cell chemotaxis and therefore can suppress inflammation and fibroblast activation. The capacity of the epithelium for CysLT synthesis is inversely related to its ability to make PGE 2 . The ASM is capable of expressing both leukotriene-synthesizing enzymes and CysLT receptors, and cytokines upregulate the receptor expression. This may be an explanation for the CysLTs promoting airway hyperresponsiveness in asthma. The CysLTs play an important role in the airway remodeling seen in persistent asthma that includes increases of airway goblet cells, mucus, blood vessels, smooth muscle, myofibroblasts, and airway fibrosis. Evidence from a mouse model of asthma demonstrated that CysLT 1 receptor antagonists inhibit the airway remodeling processes, including eosinophil trafficking to the lungs, eosinophil degranulation, T H 2 cytokine release, mucus gland hyperplasia, mucus hypersecretion, smooth muscle cell hyperplasia, collagen deposition, and lung fibrosis.

The biology of the growth plate.

Abstract: • Chondrocytes in the growth plate undergo a complex series of molecular, biochemical, and morphological changes during the process of differentiation. • Longitudinal growth depends on both proliferation and hypertrophy of chondrocytes in the growth plate. • Integrated growth factor signaling pathways control the key transition between proliferation and hypertrophy that is required for completion of the maturation process. • Terminal chondrocyte maturation is associated with programmed cell death and the secretion of matrix and other factors that promote matrix calcification and vascular invasion. • Systemic hormones interact with local growth factors and signaling pathways to influence the rate of growth and lead to closure of the growth plate. In order for paired human limbs to reach the same adult length and proportions, the longitudinal growth of the skeleton must be tightly regulated. The regulation of longitudinal growth at the growth plate occurs generally through the intimate interaction of circulating systemic hormones and locally produced peptide growth factors, the net result of which is to trigger changes in gene expression by growth plate chondrocytes. These molecular events lead to precisely orchestrated alterations in chondrocyte size, extracellular matrix components, secreted enzymes and growth factors, and receptor expression. The culmination of these events is calcification of the matrix, chondrocyte apoptosis, and completion of endochondral bone formation. This review will highlight some of the advances in genetics and cell biology in the past decade that have begun to illuminate some of the important regulatory mechanisms governing the biology of the growth plate. The growth plate can be divided into a series of anatomic zones that distinguish unique morphological and biochemical stages during the process of chondrocyte differentiation. In the resting zone, the ratio of extracellular matrix to cell volume is high and the cells are in a relatively quiescent state. In the proliferating …

Steroid receptor expression in uterine natural killer cells.

Abstract: The endometrium contains a unique subset of uterine-specific natural killer (uNK) cells, the proposed functions of which include a role in decidualization, menstruation, and implantation. These cells increase in number during the mid-late secretory phase of the menstrual cycle and are also present in large numbers in early pregnancy. The cyclical nature of uNK cell appearance suggests hormonal regulation of these cells. To date, it has not been possible to localize either estrogen receptors (ERs) or progesterone receptors (PRs) to uNK cells. In the present study, we have investigated the steroid receptor expression of uNK cells, including not only ER alpha and PR but also wild-type ER beta 1, its variant form ER beta cx/beta 2, and glucocorticoid receptor (GR) using specific monoclonal antibodies and real-time quantitative RT-PCR. mRNA encoding ER alpha, PR, ER beta cx/beta 2, ER beta 1, and GR were identified in extracts of human endometrium across the menstrual cycle and in decidua. Quantitative real-time RT-PCR demonstrated an absence of ER alpha and PR mRNA in purified uNK cells. In contrast, mRNA for ER beta cx/beta 2, ER beta 1, and GR was present in uNK cells. ER alpha, PR, ER beta cx/beta 2, ER beta 1, and GR proteins were identified in endometrial and decidual biopsies. Colocalization using specific monoclonal antibodies confirmed that uNK cells were immunonegative for ER alpha and PR protein. These cells were also immunonegative for ER beta cx/beta 2 but did express ER beta 1 and GR proteins. These results raise the possibility that estrogens and glucocorticoids could be acting directly on uNK cells through ER beta and GR, respectively, to influence gene transcription in the endometrium and decidua.

Modulation of Early Olfactory Processing by an Octopaminergic Reinforcement Pathway in the Honeybee

Abstract: Processing of olfactory information in the antennal lobes of insects and olfactory bulbs of vertebrates is modulated by centrifugal inputs that represent reinforcing events. Octopamine release by one such pathway in the honeybee antennal lobe modulates olfactory processing in relation to nectar (sucrose) reinforcement. To test more specifically what role octopamine plays in the antennal lobe, we used two treatments to disrupt an octopamine receptor from Apis mellifera brain (AmOAR) function: (1) an OAR antagonist, mianserin, was used to block receptor function, and (2) AmOAR double-stranded RNA was used to silence receptor expression. Both treatments inhibited olfactory acquisition and recall, but they did not disrupt odor discrimination. These results suggest that octopamine mediates consolidation of a component of olfactory memory at this early processing stage in the antennal lobe. Furthermore, after consolidation, octopamine release becomes essential for recall, which suggests that the modulatory circuits become incorporated as essential components of neural representations that activate odor memory.

Allelic variation in 5-HT1A receptor expression is associated with anxiety- and depression-related personality traits.

Abstract: The 5-HT1A receptor plays a critical role in the pathophysiology of anxiety and depression as well as in the mode of action of anxiolytic and antidepressant drugs. Human 5-HT1A gene transcription is modulated by a common C-1016G single nucleotide polymorphism (SNP) in its upstream regulatory region. In the present study, we evaluated the role of the HTR1A-1019 polymorphism in the modulation of individual differences in personality traits by an association study of a sample of healthy volunteers. Personality traits were assessed with two different methods, NEO personality inventory (NEO-PI-R) and Tridimensional Personality Questionnaire (TPQ). There was a significant effect of the HTR1A-1019 polymorphism on NEO Neuroticism with carriers of the G allele showing higher scores than individuals homozygous for the C variant. The effect was primarily due to associations with the Neuroticism facets Anxiety and Depression. Carriers of the G allele also exhibited higher TPQ Harm Avoidance scores. Our findings indicate a role of allelic variation in 5-HT1A receptor expression in the development and modulation of anxiety- and depression-related personality traits.

Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways.

Abstract: Erythropoietin (EPO) plays a significant role in the hematopoietic system, but the function of EPO as a neuroprotectant and anti-inflammatory mediator requires further definition. We therefore examined the cellular mechanisms that mediate protection by EPO during free radical injury in primary neurons and cerebral microglia. Neuronal injury was evaluated by trypan blue, DNA fragmentation, phosphatidylserine (PS) exposure, Akt1 phosphorylation, Bad phosphorylation, mitochondrial membrane potential, and cysteine protease activity. Microglial activation was assessed through proliferating cell nuclear antigen and PS receptor expression. EPO provides intrinsic neuronal protection that is both necessary and sufficient to prevent acute genomic DNA destruction and subsequent membrane PS exposure, since protection by EPO is completely abolished by cotreatment with an anti-EPO neutralizing antibody. Extrinsic protection by EPO is offered through the inhibition of cerebral microglial activation and the suppression of microglial PS receptor expression for the prevention of neuronal phagocytosis. In regards to microglial chemotaxis, EPO modulates neuronal poptotic membrane PS exposure necessary for microglial activation primarily through the regulation of caspase 1. EPO increases Akt1 activity, phosphorylates Bad, and maintains neuronal nuclear DNA integrity through the downstream modulation of mitochrondrial membrane potential, cytochrome c release, and caspase 1, 3, and 8-like activities. Elucidating the intrinsic and extrinsic protective pathways of EPO that mediate both neuronal integrity and inflammatory microglial activation may enhance the development of future therapies directed against acute neuronal injury. Keywords: Apoptosis, Bad, cytochrome c, cysteine proteases, erythropoietin, microglial activation, mitochondrial membrane potential, phosphatidylserine exposure, protein kinase B Introduction Initially considered to mediate primarily the proliferation and differentiation of erythroid progenitors, erythropoietin (EPO) has emerged as a versatile growth factor that may play a significant role in the nervous system. Both EPO and the erythropoietin receptor EPOR are expressed throughout the nervous system in neurons, endothelial cells, and astrocytes in the cerebral cortex, hippocampus, and the amygdala (Morishita et al., 1997; Nagai et al., 2001; Chong et al., 2002b). In neuronal injury paradigms, EPO has been shown to provide protection against toxic insults, such as ischemia and free radical injury (Bernaudin et al., 1999; Chong et al., 2002a; Wen et al., 2002). As a result, EPO has been identified as a possible candidate in the formulation of therapeutic strategies against neurodegenerative diseases. To further the development of EPO as a novel neuroprotectant against both acute and chronic neurodegenerative disease, it is first critical to understand the cellular pathways that may mediate neuronal injury and are subsequently susceptible to modulation by EPO. Oxygen-free radicals, such as nitric oxide (NO), have been established as significant precipitants of neuronal degeneration (Maiese & Vincent, 2000; Anderson et al., 2001). NO can trigger the induction of two independent apoptotic pathways that consist of nuclear DNA degradation and the exposure of membrane phosphatidylserine (PS) residues (Maiese & Vincent, 2000; Dumont et al., 2001; Lin & Maiese, 2001). Although DNA degradation in neurons may immediately impact cellular integrity (Jessel et al., 2002), the exposure of membrane PS residues in neurons can precipitate a latent cellular inflammation (Dombroski et al., 2000) and microglial phagocytosis of viable neurons (Maiese & Vincent, 2000; Hoffmann et al., 2001). Several downstream cellular pathways may ultimately determine the protective role of EPO. In particular, the serine/threonine kinase Akt1, a key determinant of cell survival, appears to be necessary for EPO to prevent apoptosis of erythroid progenitors (Uddin et al., 2000). Once activated through phosphorylation, Akt1 can inhibit the activity of several substrates that promote apoptosis, such as Bad (Blume-Jensen et al., 1998), IκB kinase α (IKKβ) (Romashkova & Makarov, 1999), the forkhead transcription factor (FHKRL1) (Brunet et al., 1999), and the glycogen synthase kinase-3β (Cross et al., 1995). The protective role of Akt1 also may be dependent upon the preservation of mitochondrial membrane integrity and the modulation of cysteine protease activity through cytochrome c. The protein Akt1 may serve to stabilize mitochondrial membrane potential and prevent the release of cytochrome c (Kennedy et al., 1999). Cellular release of NO can directly lead to mitochondrial membrane depolarization and the opening of mitochondrial permeability transition pores (Bal-Price & Brown, 2000; Chong et al., 2002a). As a result, cytochrome c is released from mitochondria and subsequently leads to the activation of a family of cysteine proteases (caspases) that include caspase 8, caspase 1, and caspase 3. Together, these cysteine proteases can lead to both DNA fragmentation and membrane PS exposure (Lin & Maiese, 2001; Mandal et al., 2002). Given the strong neuroprotective potential of EPO, we investigated the underlying cellular mechanisms controlled by EPO that may determine both the maintenance of neuronal cellular integrity and the inhibition of microglial activation to gain greater insight for the development of future neurodegenerative therapeutic strategies.

Expression and function of pro-inflammatory interleukin IL-17 and IL-17 receptor in normal, benign hyperplastic, and malignant prostate.

Abstract: INTRODUCTION AND OBJECTIVES To investigate factors involved in inflammation of the prostate besides IL-15, we screened prostatic cells and tissues for IL-17 and IL-17 receptor expression METHODS Normal prostate (n = 1), BPH (n = 19), and carcinoma (CaP, n = 12) specimens were screened for IL-17, IL-17 receptor, CD45, IL-6, and IL-8 mRNA expression The carcinoma cell lines DU145, PC3, LNCaP, and BPH-epithelial (EC), stromal cell (SC) preparations, and BPH-T-cell lines were analyzed for IL-17 production by RT-PCR and ELISA The effect of IL-17 on IL-6, IL-8, TGF-β1, and fibroblast growth factor (FGF-2) mRNA expression and/or release of SC was analyzed using real-time PCR and/or ELISA Immunohistochemistry was used to localize both IL-17 and IL-17 receptor RESULTS In the normal prostate, IL-17 expression was very weak and restricted to lymphocytes In 79% of BPH and 58% of CaP specimens, IL-17 mRNA and protein expression was increased IL-17 mRNA expression could be shown for activated BPH-T-cells and to some extend for BPH-EC Expression of IL-17 receptor was ubiquitous Release of IL-17 was shown only for activated BPH-T-cells IL-17 stimulated expression of IL-6 (13-fold) and IL-8 (26-fold) by prostatic BPH-SC In situ, however, the amount of IL-17mRNA in BPH-tissue did not correlate with the amount of IL-6 and IL-8 mRNA In CaP tissue, significant correlation was found only between the amount of IL-6 and IL-8 mRNA CONCLUSIONS Activated BPH-T-cells abundantly express IL-17 The increase of IL-17 in BPH-tissues goes hand in hand with elevated levels of IL-15, a pro-inflammatory cytokine with T-cell growth factor properties A clinical relevance of increased IL-17 expression under pathological conditions is suggested by the demonstration of significant upregulation of IL-6 and IL-8 production of prostatic SC by IL-17 Prostate 56: 171–182, 2003 © 2003 Wiley-Liss, Inc

The intrarenal renin-angiotensin system and diabetic nephropathy.

Abstract: The renin-angiotensin system (RAS) is a coordinated cascade of proteins and peptide hormones, the principal effector of which is angiotensin II (ANG II). Evidence now indicates that the kidney regulates its function via a self-contained RAS in a paracrine fashion. In diabetic nephropathy, the intrarenal generation of ANG II is increased, in spite of suppression of the systemic RAS. This increase can contribute to the progression of diabetic nephropathy via several hemodynamic, tubular and growth-promoting actions. ANG II induces insulin resistance. ANG II type-1 (AT(1)) and type-2 (AT(2)) receptors are downregulated in chronic diabetes, but decreased AT(2) receptor expression might contribute to early diabetic nephropathy by reducing AT(2) receptor-mediated beneficial actions that are counter-regulatory to those of the AT(1) receptor. AT(2) receptor stimulation might account for part of the renal protection seen with AT(1) receptor blockade. A rat model of accelerated diabetic nephropathy is the (mREN-2) 27 renin transgenic rat treated with streptozotocin in which both the intrarenal and extrarenal RAS is activated.

Estrogen receptor alpha mRNA in human skeletal muscles.

Abstract: Introduction/purpose To explain the effect of estrogen on skeletal muscle, the presence of estrogen receptor alpha mRNA (ERalpha mRNA) was investigated in human skeletal muscle. Methods The highly sensitive technique of nested reverse transcriptase-polymerase chain reaction (nested RT-PCR) was applied on a variety of tissue samples of both sexes: women (deltoid, pectoral, and uterus muscles) (N= 3) and men (deltoid muscle) (N= 3). The total ribonucleic acid was isolated from each tissue sample, reverse transcribed in a thermocycler, and nested PCR was then performed with specific primers. The by-products were analyzed by agarose gel electrophoresis. Internal standard 28S was simultaneously amplified. The ERalpha mRNA level was quantitated by using the ERalpha mRNA/28S mRNA ratio. Results The expected 204-bp product corresponding to ERalpha was amplified in all tested tissue samples, i.e., deltoid, pectoral, and uterine muscles from women and deltoid muscle from men. The ERalpha mRNA/28S mRNA ratios indicating the receptor expression levels in deltoid muscle from men and women were 0.945 +/- 0.393 (mean +/- SD) (N= 3) and 0.973 +/- 0.136 (mean +/- SD) (N= 2), respectively. Conclusions In conclusion, the nested RT-PCR technique identified the presence of transcript encoding ERalpha mRNA in human skeletal muscles. Semi-quantification did not reveal gender difference.

Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells: A possibility of tyrosine kinase inhibitor of growth factor

Abstract: Angiotensin II (A-II) receptor (AT(1) receptor) blockers (ARB) are a class of antihypertensive agent. It is known that they suppress signal transduction pathways mediated by growth factors [e.g., epidermal growth factor (EGF)] through the AT(1) receptor in vascular endothelial cells. In the present study, we demonstrated that A-II activates the cell proliferation of prostate cancer as well as EGF. In addition, we showed that A-II induces the phosphorylations of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) in prostate cancer cells. In contrast, ARB was shown to inhibit the proliferation of prostate cancer cells stimulated with EGF or A-II, the mechanism of which is through the suppression of MAPK or STAT3 phosphorylation by ARB. Oral administration of ARB to nude mice inhibited the growth of prostate cancer xenografts in both androgen-dependent and androgen-independent cells in a dose-dependent manner. Microvessel density was reduced in xenografts treated with ARB, which means ARB inhibits the vascularization of xenografts. Expression of AT(1) receptor mRNA was examined by reverse transcription-PCR using 10 pairs of human prostate cancer and normal prostate tissues. AT(1) receptor expression in human prostate cancer tissue was higher (9 of 10 cases) than that in normal prostate tissue. These results suggest the possibility that ARB is a novel therapeutic class of agents for prostate cancer, especially hormone-independent tumors.

Additive Effects of PDGF Receptor β Signaling Pathways in Vascular Smooth Muscle Cell Development

Abstract: The platelet-derived growth factor β receptor (PDGFRβ) is known to activate many molecules involved in signal transduction and has been a paradigm for receptor tyrosine kinase signaling for many years. We have sought to determine the role of individual signaling components downstream of this receptor in vivo by analyzing an allelic series of tyrosine–phenylalanine mutations that prevent binding of specific signal transduction components. Here we show that the incidence of vascular smooth muscle cells/pericytes (v/p), a PDGFRβ-dependent cell type, can be correlated to the amount of receptor expressed and the number of activated signal transduction pathways. A decrease in either receptor expression levels or disruption of multiple downstream signaling pathways lead to a significant reduction in v/p. Conversely, loss of RasGAP binding leads to an increase in this same cell population, implicating a potential role for this effector in attenuating the PDGFRβ signal. The combined in vivo and biochemical data suggest that the summation of pathways associated with the PDGFRβ signal transduction determines the expansion of developing v/p cells.

Changes in ghrelin and ghrelin receptor expression according to feeding status.

Abstract: Ghrelin, a newly identified gut hormone, has been implicated in the regulation of food intake and energy homeostasis. This study was undertaken to investigate changes in expression levels of stomach ghrelin as well as of ghrelin receptor in the hypothalamus and pituitary glands according to feeding state. Stomach ghrelin mRNA levels were increased by 48 h fasting but decreased by re-feeding. The ghrelin receptor mRNA levels of 48 h fasted rats were 8 times higher in the hypothalamus and 3 times higher in the anterior pituitary gland than levels in fed rats. In summary, not only stomach ghrelin, but also hypothalamic ghrelin receptor mRNA expression, increased during a fast. Such as enhanced ghrelin receptor expression could contribute to the amplification of ghrelin action in a negative-energy balance state.