DOCSLIB.ORG

Developmental Expression Oe Neurotensin and Galanin In

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Developmental Expression Oe Neurotensin and Galanin In Biomedical Research 16 (5) 281-286, 1995 i 1| i 2 DEVELOPMENTAL EXPRESSION OE NEUROTENSIN AND GALANIN § IN THE RAT GASTROINTESTINAL TRACT 2 i i MUNEO OKA‘, NIMA KHANDAN-—NIA2, PHILIP JoNEs2, MOHAMMAD GHATEI2 and STEPHEN ROBERT BLOOM2 ‘Department of Endocrinology, Internal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-02, Japan, and 2Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 ONN, U.K. ABSTRACT To characterize and compare the developmental patterns of neurotensin (NT) and galanin (GAL) expression in the gastrointestinal tract, we measured both peptide content and mRNA concentrations in different regions of the rat gastrointestinal tract at different times during fetal and postnatal development. The abundance of NT mRNA in the jejunum and ileum increased from birth and peaked on day 7, subsequently decreased by day 21. In con- trast, expression of NT mRNA in the stomach and colon remained very low. Changes in NT peptide content parallelled that in NT mRNA. On the other hand, the abundance of GAL mRNA, which was expressed in all regions of the gastrointestinal tract, gradually increased until day 21 following birth. GAL peptide content increased up until day 7; thereafter, the levels of this peptide remained relatively unchanged. Thus, the gene expres- sion of NT and GAL each demonstrates a specific pattern of tissue distribution and a dif- ferent developmental pattern. These data suggest that NT and GAL gene expression and peptide content are developmentally regulated and that NT and GAL each play a different role in the gastrointestinal tract during development. Previous studies have suggested important roles for distribution of these neuropeptides during gut several neuropeptides in maintaining the functional development should provide a better understanding and structural integrity of the gut. For example, of their roles in the gut. The purpose of this study neurotensin (NT), a gut tridecapeptide localized was to characterize and compare the developmental mainly in the distal small bowel (14, 25, 32) and pattern of NT and GAL expression in the rat gas- brain of adults (24), is an important hormone regu- trointestinal tract. To this end, we measured both lating gut motility, secretion, and mucosal growth immunoreactivity and mRNA concentrations in (1, 6, 31). Expression of such neuropeptides in the different regions of the rat gastrointestinal tract at gut is likely to be regulated during development, different times during fetal and postnatal develop- when rapid changes occur in gut structure and func- ment. tion. In fact, lower levels of NT mRNA have been found in the fetal rat ileum than in the adult (IO); MATERIALS AND METHODS similarly, fewer NT-immunoreactive cells have been found in the fetal human small bowel than in Animals the adult (28). In contrast, galanin (GAL), a 29 Eighty male Wistar rats were used in this amino acid gut peptide originally isolated from study. Twenty-one-day-old rats were kept five to porcine intestine that has been shown to be a cage and fed ad lib. Newborn animals were involved in the regulation of gut motility (3, 5, 7, kept with their mother until sacrificed. Fetal 11, 12, 26, 29), has been found to decrease after rats (—1 day) were removed immediately follow- birth in the rat stomach and duodenum (13). Thus, ing the death of their mother and decapitated elucidation of any changes in the expression and instantly. .
Load more

Recommended publications
  • Calcitonin Gene Products and the Kidney
    Kiinische Klin Wochenschr (1989) 67:870-875 W°chenchrif t © Springer-Verlag 1989 Calcitonin Gene Products and the Kidney A. Kurtz 1, R. Muff z, and J.A. Fischer z 1 Physiologic Institute, University of Ziirich, Switzerland 2 Research Laboratory for Calcium Metabolism, Departments of Orthopedic Surgery and Medicine, University of Ziirich, Ziirich, Switzerland Summary. Calcitonin gene-related peptide (CGRP) Calcitonin and CGRP are single chain polypep- is localized in capsaicin-sensitive nerve fibres in the tides consisting of 32 and 37 amino acids, respec- kidney and urogenital tract whereas calcitonin tively. They have in common amino-terminal ring reaches the kidney through the general circulation. structures linked by disulfide bridges and the car- Systemic infusion of CGRP and perfusion of iso- boxyltermini are amidated. In man, CGRP shares lated rat kidney reduces vascular resistance, and 16% structural homology with calcitonin whereas increases renal blood flow and glomerular filtra- the homology between CGRP-I and -II is 92% tion. CGRP stimulates renin secretion in vivo and [13]. As a result, distinct receptors for calcitonin in vitro and inhibits contraction of isolated rat me- and CGRP have been identified [7, 11, 33, 42]. sangial cells by angiotensin II. Calcitonin does not Human CGRP-I and -II, due to their high homolo- affect vascular resistance, renal blood flow and glo- gy, crossreact almost completely, but subtle differ- merular filtration, and is tess potent in stimulating ences in the distribution of human CGRP-I and renin secretion, and does not alter contraction of -II binding sites have been observed on receptor isolated rat mesangial cells by angiotensin II.
    [Show full text]
  • The Role of Kisspeptin Neurons in Reproduction and Metabolism
    238 3 Journal of C J L Harter, G S Kavanagh Kisspeptin, reproduction and 238:3 R173–R183 Endocrinology et al. metabolism REVIEW The role of kisspeptin neurons in reproduction and metabolism Campbell J L Harter*, Georgia S Kavanagh* and Jeremy T Smith School of Human Sciences, The University of Western Australia, Perth, Western Australia, Australia Correspondence should be addressed to J T Smith: [email protected] *(C J L Harter and G S Kavanagh contributed equally to this work) Abstract Kisspeptin is a neuropeptide with a critical role in the function of the hypothalamic– Key Words pituitary–gonadal (HPG) axis. Kisspeptin is produced by two major populations of f Kiss1 neurons located in the hypothalamus, the rostral periventricular region of the third f hypothalamus ventricle (RP3V) and arcuate nucleus (ARC). These neurons project to and activate f fertility gonadotrophin-releasing hormone (GnRH) neurons (acting via the kisspeptin receptor, f energy homeostasis Kiss1r) in the hypothalamus and stimulate the secretion of GnRH. Gonadal sex steroids f glucose metabolism stimulate kisspeptin neurons in the RP3V, but inhibit kisspeptin neurons in the ARC, which is the underlying mechanism for positive- and negative feedback respectively, and it is now commonly accepted that the ARC kisspeptin neurons act as the GnRH pulse generator. Due to kisspeptin’s profound effect on the HPG axis, a focus of recent research has been on afferent inputs to kisspeptin neurons and one specific area of interest has been energy balance, which is thought to facilitate effects such as suppressing fertility in those with under- or severe over-nutrition.
    [Show full text]
  • Neurotensin Activates Gabaergic Interneurons in the Prefrontal Cortex
    The Journal of Neuroscience, February 16, 2005 • 25(7):1629–1636 • 1629 Behavioral/Systems/Cognitive Neurotensin Activates GABAergic Interneurons in the Prefrontal Cortex Kimberly A. Petrie,1 Dennis Schmidt,1 Michael Bubser,1 Jim Fadel,1 Robert E. Carraway,2 and Ariel Y. Deutch1 1Departments of Pharmacology and Psychiatry, Vanderbilt University Medical Center, Nashville, Tennessee 37212, and 2Department of Physiology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655 Converging data suggest a dysfunction of prefrontal cortical GABAergic interneurons in schizophrenia. Morphological and physiological studies indicate that cortical GABA cells are modulated by a variety of afferents. The peptide transmitter neurotensin may be one such modulator of interneurons. In the rat prefrontal cortex (PFC), neurotensin is exclusively localized to dopamine axons and has been suggested to be decreased in schizophrenia. However, the effects of neurotensin on cortical interneurons are poorly understood. We used in vivo microdialysis in freely moving rats to assess whether neurotensin regulates PFC GABAergic interneurons. Intra-PFC administra- tion of neurotensin concentration-dependently increased extracellular GABA levels; this effect was impulse dependent, being blocked by treatment with tetrodotoxin. The ability of neurotensin to increase GABA levels in the PFC was also blocked by pretreatment with 2-[1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)pyrazole-3-yl)carbonylamino]tricyclo(3.3.1.1.3.7)decan-2-carboxylic acid (SR48692), a high-affinity neurotensin receptor 1 (NTR1) antagonist. This finding is consistent with our observation that NTR1 was localized to GABAergic interneurons in the PFC, particularly parvalbumin-containing interneurons. Because neurotensin is exclusively localized to dopamine axons in the PFC, we also determined whether neurotensin plays a role in the ability of dopamine agonists to increase extracellular GABA levels.
    [Show full text]
  • Serum Levels of Spexin and Kisspeptin Negatively Correlate with Obesity and Insulin Resistance in Women
    Physiol. Res. 67: 45-56, 2018 https://doi.org/10.33549/physiolres.933467 Serum Levels of Spexin and Kisspeptin Negatively Correlate With Obesity and Insulin Resistance in Women P. A. KOŁODZIEJSKI1, E. PRUSZYŃSKA-OSZMAŁEK1, E. KOREK4, M. SASSEK1, D. SZCZEPANKIEWICZ1, P. KACZMAREK1, L. NOGOWSKI1, P. MAĆKOWIAK1, K. W. NOWAK1, H. KRAUSS4, M. Z. STROWSKI2,3 1Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, Poznan, Poland, 2Department of Hepatology and Gastroenterology & The Interdisciplinary Centre of Metabolism: Endocrinology, Diabetes and Metabolism, Charité-University Medicine Berlin, Berlin, Germany, 3Department of Internal Medicine, Park-Klinik Weissensee, Berlin, Germany, 4Department of Physiology, Karol Marcinkowski University of Medical Science, Poznan, Poland Received August 18, 2016 Accepted June 19, 2017 On-line November 10, 2017 Summary Corresponding author Spexin (SPX) and kisspeptin (KISS) are novel peptides relevant in P. A. Kolodziejski, Department of Animal Physiology and the context of regulation of metabolism, food intake, puberty and Biochemistry, Poznan University of Life Sciences, Wolynska Street reproduction. Here, we studied changes of serum SPX and KISS 28, 60-637 Poznan, Poland. E-mail: [email protected] levels in female non-obese volunteers (BMI<25 kg/m2) and obese patients (BMI>35 kg/m2). Correlations between SPX or Introduction KISS with BMI, McAuley index, QUICKI, HOMA IR, serum levels of insulin, glucagon, leptin, adiponectin, orexin-A, obestatin, Kisspeptin (KISS) and spexin (SPX) are peptides ghrelin and GLP-1 were assessed. Obese patients had lower SPX involved in regulation of body weight, metabolism and and KISS levels as compared to non-obese volunteers (SPX: sexual functions. In 2014, Kim and coworkers showed that 4.48±0.19 ng/ml vs.
    [Show full text]
  • Purification of a Galanin Receptor from Pig Brain
    Proc. Natl. Acad. Sci. USA Vol. 90, pp. 3845-3849, May 1993 Neurobiology Purification of a galanin receptor from pig brain YAOHUI CHEN*, ALAIN FOURNIERt, ALAIN COUVINEAU*, MARC LABURTHE*, AND BRIGITTE AMIRANOFF*t *Laboratoire de Biologie and Physiologie des Cellules Digestives, Institut National de la Sant6 et de la Recherche Mddicale, U 239, 16 Rue Henri Huchard-75018 Paris, France; and tUniversitd du Quebec, Institut National de la Recherche Scientifique, INRS-Santd, 245 Boulevard Hymus, Pointe Claire, Qudbec, H9R1G6, Canada Communicated by Tomas Hokfelt, January 4, 1993 ABSTRACT A galanin receptor protein was solubilized lished data), we report the purification of a galanin receptor with 3-[(3-cholamidopropyl)dimethylammonio]-1-propane- from pig brain, a rich source of receptors that is available in sulfonate (CHAPS) from pig brain membranes and then pu- large amounts. This represents a basic step toward knowl- rified by single-step affinity chromatography. The product edge of the pharmacology and biochemistry of galanin re- exhibits saturable and specific binding for galanin with a ceptors and should lead to a better understanding of their binding activity of 17 nmol/mg of protein and a dissociation expression in the organism. constant (Kd) of 10 nM. This represents a 300,000-fold puri- fication over the detergent-solubilized fraction with a final recovery of 31% of the initial membrane galanin binding METHODS activity. Gel electrophoresis of the affinity-purified material Materials. Synthetic porcine galanin, glucagon, vasoactive showed a single polypeptide of 54 kDa by silver staining and intestinal peptide, synthetic neurotensin, substance P, baci- after radioiodination. Cross-linking of a purified fraction af- tracin, leupeptin, pepstatin A, GTP, GDP, guanosine 5'-[13,v- rmity-labeled with 125I-labeled galanin revealed a single band imido]triphosphate, cholesteryl hemisuccinate, 3-[(3-cholami- for the galanin-receptor complex at 57 kDa.
    [Show full text]
  • Reorganization of Neural Peptidergic Eminence After Hypophysectomy
    The Journal of Neuroscience, October 1994, 14(10): 59966012 Reorganization of Neural Peptidergic Systems Median Eminence after Hypophysectomy Marcel0 J. Villar, Bjiirn Meister, and Tomas Hiikfelt Department of Neuroscience, The Berzelius Laboratory, Karolinska Institutet, Stockholm, 171 77 Sweden Earlier studies have shown the formation of a novel neural crease to a final stage of a few, strongly immunoreactive lobe after hypophysectomy, an experimental manipulation fibers in the external layer at longer survival times. Vaso- that causes transection of neurohypophyseal nerve fibers active intestinal polypeptide (VIP)- and peptide histidine- and removal of pituitary hormones. The mechanisms that isoleucine (PHI)-IR fibers in hypophysectomized animals had underly this regenerative process are poorly understood. already contacted portal vessels 5 d after hypophysectomy, The localization and number of peptide-immunoreactive and from then on progressively increased in numbers. Fi- (-IR) fibers in the median eminence were studied in normal nally, most of the peptide fibers described above formed rats and in rats at different times of survival after hypophy- dense innervation patterns around the large blood vessels sectomy using indirect immunofluorescence histochemistry. along the lateral borders of the median eminence. The number of vasopressin (VP)-IR fibers increased in the The present results show that hypophysectomy induces external layer of the median eminence in 5 d hypophysec- a wide variety of changes in hypothalamic neurosecretory tomized rats. Oxytocin (OXY)-IR fibers decreased in the in- fibers. Not only is the expression of several peptides in these ternal layer and progressively extended into the external fibers modified following different survival times, but a re- layer.
    [Show full text]
  • And Neurotensin-Immunoreactive Cells in the Gastrointestinal Tract of the Chicken
    Histol Histopath (1989) 4: 55-62 Histology and Histopathology The distribution and ontogeny of gastrin/CCK-, somatostatin- and neurotensin-immunoreactive cells in the gastrointestinal tract of the chicken B.C. Alison Department of Anatomy, Medical School, University of the Witwatersrand,Johannesburg, South Africa Summary. The distribution and time of appearance of wide variety of invertebrates and of vertebrates, cells with gastrin1CCK-, neurotensin- and somatostatin- especially mammals, (Rufener et al., 1975; Sundler et like immunoreactivity were studied in samples from al., 1977; Alumets et al., 1977; Helmstaedter et al., 1977; eight regions of the gastrointestinal tract of chick Seino et al., 1979). Studies on avian gut have been embryos from 11 days of incubation to hatching. No conducted at hatching (Rawdon and Andrew, 1981) and immunoreactive cells were found in any region at 11 thereafter in young birds, (Larsson et al., 1974) and days of incubation. Somatostatin- and neurotensin- adults (Aitken, 1958; Yamada et al., 1979). immunoreactive cells appeared for the first time in the Immunocytochemical studies have also demonstrated proventriculus, pyloric region and duodenum at 12 days immunoreactive cells of various types in early rat and of incubation with cells immunoreactive for neurotensin human foetal gut (Larsson et al., 1975; Dubois et al., occurring in the rectum at the same stage. GastrinICCK- 1976; Dubois et al., 1976; Larsson et al., 1977; Dupouy et immunoreactive cells were detected in the small intestine al., 1983; Kataoka et al., 1985). There is, however, much first at 14 days and in the pyloric region two days later. less published work on embryonic avian material; that of Cells immunoreactive for somatostatin and neurotensin Sundler et al.
    [Show full text]
  • Male-Predominant Galanin Mediates Androgen-Dependent Aggressive
    RESEARCH ARTICLE Male-predominant galanin mediates androgen-dependent aggressive chases in medaka Junpei Yamashita1, Akio Takeuchi1, Kohei Hosono1†, Thomas Fleming1, Yoshitaka Nagahama2, Kataaki Okubo1* 1Department of Aquatic Bioscience, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan; 2Division of Reproductive Biology, National Institute for Basic Biology, Okazaki, Japan Abstract Recent studies in mice demonstrate that a subset of neurons in the medial preoptic area (MPOA) that express galanin play crucial roles in regulating parental behavior in both sexes. However, little information is available on the function of galanin in social behaviors in other species. Here, we report that, in medaka, a subset of MPOA galanin neurons occurred nearly exclusively in males, resulting from testicular androgen stimulation. Galanin-deficient medaka showed a greatly reduced incidence of male–male aggressive chases. Furthermore, while treatment of female medaka with androgen induced male-typical aggressive acts, galanin deficiency in these females attenuated the effect of androgen on chases. Given their male-biased and androgen- dependent nature, the subset of MPOA galanin neurons most likely mediate androgen-dependent male–male chases. Histological studies further suggested that variability in the projection targets of the MPOA galanin neurons may account for the species-dependent functional differences in these evolutionarily conserved neural substrates. *For correspondence: [email protected] Present address: †School of Life Science and Technology, Tokyo Introduction Institute of Technology, Yokohama, Japan Almost all animals interact socially with conspecifics at some stage of their lives (e.g. for territorial/ resource disputes, mating, and parenting) (Hofmann et al., 2014; Chen and Hong, 2018).
    [Show full text]
  • Neurotransmitter and Neuropeptide Regulation of Mast Cell Function
    Xu et al. Journal of Neuroinflammation (2020) 17:356 https://doi.org/10.1186/s12974-020-02029-3 REVIEW Open Access Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review Huaping Xu1, Xiaoyun Shi2, Xin Li3, Jiexin Zou4, Chunyan Zhou5, Wenfeng Liu5, Huming Shao5, Hongbing Chen5 and Linbo Shi4* Abstract The existence of the neural control of mast cell functions has long been proposed. Mast cells (MCs) are localized in association with the peripheral nervous system (PNS) and the brain, where they are closely aligned, anatomically and functionally, with neurons and neuronal processes throughout the body. They express receptors for and are regulated by various neurotransmitters, neuropeptides, and other neuromodulators. Consequently, modulation provided by these neurotransmitters and neuromodulators allows neural control of MC functions and involvement in the pathogenesis of mast cell–related disease states. Recently, the roles of individual neurotransmitters and neuropeptides in regulating mast cell actions have been investigated extensively. This review offers a systematic review of recent advances in our understanding of the contributions of neurotransmitters and neuropeptides to mast cell activation and the pathological implications of this regulation on mast cell–related disease states, though the full extent to which such control influences health and disease is still unclear, and a complete understanding of the mechanisms underlying the control is lacking. Future validation of animal and in vitro models also is needed, which incorporates the integration of microenvironment-specific influences and the complex, multifaceted cross-talk between mast cells and various neural signals. Moreover, new biological agents directed against neurotransmitter receptors on mast cells that can be used for therapeutic intervention need to be more specific, which will reduce their ability to support inflammatory responses and enhance their potential roles in protecting against mast cell–related pathogenesis.
    [Show full text]
  • Targeting Neuropeptide Receptors for Cancer Imaging and Therapy: Perspectives with Bombesin, Neurotensin, and Neuropeptide-Y Receptors
    Journal of Nuclear Medicine, published on September 4, 2014 as doi:10.2967/jnumed.114.142000 CONTINUING EDUCATION Targeting Neuropeptide Receptors for Cancer Imaging and Therapy: Perspectives with Bombesin, Neurotensin, and Neuropeptide-Y Receptors Clément Morgat1–3, Anil Kumar Mishra2–4, Raunak Varshney4, Michèle Allard1,2,5, Philippe Fernandez1–3, and Elif Hindié1–3 1CHU de Bordeaux, Service de Médecine Nucléaire, Bordeaux, France; 2University of Bordeaux, INCIA, UMR 5287, Talence, France; 3CNRS, INCIA, UMR 5287, Talence, France; 4Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, DRDO, New Delhi, India; and 5EPHE, Bordeaux, France Learning Objectives: On successful completion of this activity, participants should be able to list and discuss (1) the presence of bombesin receptors, neurotensin receptors, or neuropeptide-Y receptors in some major tumors; (2) the perspectives offered by radiolabeled peptides targeting these receptors for imaging and therapy; and (3) the choice between agonists and antagonists for tumor targeting and the relevance of various PET radionuclides for molecular imaging. Financial Disclosure: The authors of this article have indicated no relevant relationships that could be perceived as a real or apparent conflict of interest. CME Credit: SNMMI is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNMMI designates each JNM continuing education article for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, SAM, and other credit types, participants can access this activity through the SNMMI website (http://www.snmmilearningcenter.org) through October 2017.
    [Show full text]
  • Localization and Role of Galanin in the Thyroid Gland of Podarcis Sicula Lizard
    JOURNAL OF EXPERIMENTAL ZOOLOGY 311A:199–206 (2009) A Journal of Integrative Biology Localization and Role of Galanin in the Thyroid Gland of Podarcis sicula Lizard (Reptilia, Lacertide) ROSARIA SCIARRILLO1Ã, ANNA CAPALDO2, SALVATORE VALIANTE2, 2 2 VINCENZA LAFORGIA , AND MARIA DE FALCO 1Department of Biological and Environmental Sciences, University of Sannio, Benevento, Italy 2Department of Evolutive and Comparative Biology, University of Naples ‘‘Federico II,’’ Naples, Italy ABSTRACT Galanin (GAL) is a 29-amino acid residue neuropeptide, which was initially isolated from porcine intestine extracts and since then, widely found in a variety of vertebrate organs, in correlation with multiple neuro-hormonal actions exerted and so receiving a constantly growing attention. Moreover, although the studies undertaken so far suggest a local intrathyroidal peptidergic regulatory action, the exact role of GAL on thyroid gland remains to be established. The aim of this study was to determine in the lizard, Podarcis sicula, (1) the presence of GAL immunoreactivity in the thyroid gland and (2) the short- and long-term effects of in vivo GAL administration by intraperitoneal injection on thyroid gland physiology. First of all, the presence of GAL in the thyroid gland of P. sicula was demonstrated by immunohistochemical technique (avidin–biotin–peroxidase complex—ABC method). Second, the role of GAL in the control of thyroid gland activity was studied in vivo using light microscopy (LM) technique coupled to a specific radioimmunoassay for thyroid-stimulating hormone (TSH) and thyroid hormones (T4 and T3). Prolonged GAL administration [(0.4 mg/100 g body wt)/day] increased T4 and T3 release, but decreased the plasma concentration of TSH.
    [Show full text]
  • Galanin, Neurotensin, and Phorbol Esters Rapidly Stimulate Activation of Mitogen-Activated Protein Kinase in Small Cell Lung Cancer Cells
    [CANCER RESEARCH 56. 5758-5764, December 15, 1996] Galanin, Neurotensin, and Phorbol Esters Rapidly Stimulate Activation of Mitogen-activated Protein Kinase in Small Cell Lung Cancer Cells Thomas Seufferlein and Enrique Rozengurt' Imperial Cancer Research Fund, P. 0. Box 123, 44 Lincoln ‘sinnFields, London WC2A 3PX, United Kingdom ABSTRACT and p44me@@k,aredirectly activated by phosphorylation on specific tyrosine and threonine residues by the dual-specificity MEKs, of Addition of phorbol 12,13-dibutyrate (PDB) to H 69, H 345, and H 510 which at least two isofonus, MEK-1 and MEK-2, have been identified small cell lung cancer (SCLC) cells led to a rapid concentration- and in mammalian cells (12—14).Several pathways leading to MEK acti time-dependent increase in p42―@ activity. PD 098059 [2-(2'-amino 3'-methoxyphenyl)-oxanaphthalen-4-one], a selective inhibitor of mitogen vation have been described. Tyrosine kinase receptors induce p42r@a@@@( activated protein kinase (MAPK) kinase 1, prevented activation of via a son of sevenless (SOS)-mediated accumulation of p2l@-GTP, p42maPk by PDB in SCLC cells. PDB also stimulated the activation of which then activates a kinase cascade comprising p74@', MEK, and p90r$k, a major downstream target of p42―@. The effect of PDB on both p42Jp44maPk (10, 11). Activation of seven transmembrane domain p42―@and p90rsk activation could be prevented by down-regulation of receptors also leads to p42@'@ activation, but the mechanisms in protein kinase C (PKC) by prolonged pretreatment with 800 aM PDB or volved are less clear, although both p2l@- and PKC-dependent treatment of SCLC cells with the PKC inhibitor bisindolylmaleinside (GF pathways have been implicated (15—20).Activated MAPKs directly 109203X), demonstrating the involvement ofphorbol ester-sensitive PKCS phosphorylate and activate various enzymes, e.g., p90@ (21, 22), and In the signaling pathway leading to p42 activation.
    [Show full text]