DOCSLIB.ORG

Immunoh Foil Istatin Istochemical Localiza in Human Tissues Tion of Activin A

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Immunoh Foil Istatin Istochemical Localiza in Human Tissues Tion of Activin A Endocrine Journal 1996, 43(4), 375-385 immunoh istochemical Localiza tion of Activin A and Foil istatin in Human Tissues MIcHIKO WADA, YASUMI SHINTANI, MASAAKI KOSAKA, TosHIAKI SANO*, KAzuo HIZAWA*, AND SHIRO SAITO First Department of Internal Medicine and *First Department of Pathology, School of Medicine, The University of Tokushima, Tokushima 770, Japan Abstract. We immunohistochemically investigated the localization of activin A and follistatin in various human tissues with specific antibodies to recombinant human (rh-) activin A and rh-follistatin. Specific immunostaining of activin A was detected in Leydig and Sertoli cells of the testis. In the ovary, granulosa cells of mature follicle and luteal cells of the corpus luteum stained for activin A. Immunoreactive activin A was present in somatotrophs of the pituitary gland and insulin-positive B cells of the pancreatic islets. Immunoreactivity for activin A was also found in thyroid follicular cells, adrenocortical cells, neuronal cells of the cerebrum and monocytoid cells in the bone marrow. Follistatin, an activin-binding protein, was immunostained in the same tissues as activin A. These findings indicated that activin A and follistatin are widely distributed in human tissues, suggesting that activin plays important roles as a common regulator in various tissues under the control of co-existing follistatin. Key words: Activin , Follistatin, Inhibin, Immunohistochemistry (Endocrine Journal 43: 375-385,1996) ACTIVIN and inhibin are both dimeric proteins logical activities. It regulates erythropoiesis [6], originally isolated from porcine follicular fluid and promotes nerve cell survival [7], inhibits neural able to influence FSH release from the pituitary differentiation [8], induces embryonic mesoderm [1-3]. There are three forms of activin, activin A, formation [9], and stimulates insulin secretion [10]. activin AB and activin B, each of which consists of Activin subunits and follistatin mRNAs have been two subunits (flA or f3B) [1-3]. Inhibin is com- detected in gonadal and various extragonadal tis- posed of one a-subunit and one fJ-subunit (/3A or sues [11, 12], implying that they have diverse fB) [2, 3]. All of these subunits are structually functions. similar, and activins and inhibin belong to the It has been difficult to obtain a specific antibody transforming growth factor-f3 (TGF-f3) superfamily to activin because its structure is highly homolo- [3, 4]. Follistatin, an activin-binding protein, is a gous in various species and it shares a common glycosylated single-chain protein also isolated from /3-subunit with inhibin. Since we succeeded in pre- ovarian follicular fluid and has the potency to sup- paring for specific polyclonal antibodies to press FSH release by binding to activin [5]. recombinant human (rh-) activin A and rh-follista- Activin has been reported to exhibit various bio- tin [13, 14], we immunohistochemically examined the localization of activin A and follistatin in vari- ous human tissues to elucidate the distribution and Received: December 25, 1995 Accepted: March 7, 1996 possible roles of activin and follistatin in vivo. We Correspondence to: Dr. Michiko WADA, First Department also examined the distribution of the inhibin u- of Internal Medicine, School of Medicine, The University subunit to compare it with those of activin A and of Tokushima, Kuramoto-cho 3, Tokushima 770, Japan follistatin. 376 WADA et a!. Materials and Methods Immunohistochemistry Tissue preparation Three ,um thick paraffin-embedded sections were stained by the streptoavidin-biotin peroxidase com- Human normal tissues obtained at autopsy or plex method (Histofine SAB-PO kit; Nichirei Co., surgery were fixed in 10% buffered formalin and Tokyo, Japan). The deparaffinized sections were embedded in paraffin. The ages of 10 patients at immersed in 0.3% H2O2 in 100% methanol for 30 autopsy ranged from 18 to 69 years (mean, 56 years, min at room temperature to block endogenous per- 8 men and 2 women). None of the patients had oxidase activity. Possible background staining was received hormone therapy. Each type of organ also blocked by applying normal goat serum for was obtained from at least 3 patients. Ovaries were 20 min at room temperature. Anti-activin A anti- obtained from 12 patients (between 25 and 45 years body was applied to the sections at 1:1000 dilution of age; mean 36 years) at the time of oophorecto- in phosphate-buffered saline, and followed by in- my for ovarian cyst or uterine myoma. Testes cubation at 4 °C in a moist chamber for 12 h. They biopsied for sterility in 3 patients of the 4th de- were then treated with biotinylated goat anti-rab- cade, and removed by castration from 3 patients bit IgG conjugated to streptoavidin-biotinylated of the 7th decade were used. Bone marrow speci- peroxidase and developed with DAB hydrogen mens were obtained from 3 healthy men aged peroxide substrate (45 mg 3,3' DAB in 150 ml Tris- twenty. Informed consent was obtained from all buffered saline solution containing 3 p/ H202). The these patients. sections were counterstained with methyl green or hematoxylin. Control sections were treated in the Antibody preparation same way, except that the antibody was preab- sorbed with 500 jig rh-activin A with affinity Anti-activin A polyclonal antibody was generat- chromatography units (Nalgene Co., USA). This ed with rh-activin A supplied by Ajinomoto Central preabsorbed antibody did not show any signifi- Research Laboratories, Kawasaki, Japan as de- cant reaction with rh-activin A on evaluation by scribed [13]. This antibody cross-reacted only with ELISA. Commercial preparations of antibodies bovine inhibin (3.2%) and porcine activin AB were also used in studies of the co-localization of (10.0%), but not with porcine activin B (<0.5%) [13]. 13-FSH(1:100 dilution, Immunotech, France), J3-LH The addition of excessive follistatin minimally af- (1:100 dilution, Immunotech), GH (1:800 dilution, fected ir-activin A recovery in the DAKO, Denmark), PRL (1:100, dilution, Immuno- radioimmunoassay (unpublished data), and the tech), fl-TSH (1:100 dilution, Immunotech) and presence of activin-follistatin complex was suggest- ACTH (1:1000 dilution, UCB-bioproducts, USA) in ed on gel chromatographic analysis of serum and adjacent sections of the pituitary, and of insulin follicular fluid [13, 14]. Taken together with these (1:400 dilution, DAKO) and glucagon (1:1000 dilu- findings, this polyclonal antibody was supposed tion, DAKO) in adjacent sections of pancreatic to detect both follistatin-bound and -unbound ac- islets. The localizations of follistatin and inhibin tivin A. A polyclonal antibody to rh-follistatin were examined by the same procedure with anti- (Ajinomoto Central Research Laboratories) was also follistatin antibody (1:200 dilution) and anti-inhibin prepared with the same procedure as that for ac- a-subunit antibody (1:200 dilution). tivin A [15]. By the immunoradiometric assay this antibody did not cross-react with bovine inhibin and rh-activin A (<0.5%). A mouse monoclonal Results antibody to bovine inhibin a-subunit was a gift from Prof. Y. Hasegawa (Kitasato University School The localizations of immunoreactive (ir-) activin of Veterinary Medicine and Animal Sciences, Tow- A, follistatin and inhibin a-subunit in human tis- ada, Japan) [16] and was used for the comparison. sues are summarized in Table 1. Activin A and follistatin were almost concurrently localized in various tissues such as the reproductive system, ACTIVIN AND FOLLISTATIN IN HUMAN TISSUES 377 Table 1. Localization of activin A , follistatin and the inhibin a-subunit in human tissues endocrine organs, brain and bone marrow. In the pituitary, adenohypophysial cells were In the testis, intense immunostaining for activin immunostained with anti-activin A antibody. Im- A was observed diffusely in the cytoplasm of Ley- munohistochemical studies with adjacent sections dig cells, most of which were grouped in clusters, revealed that ir-activin A (Fig. 3A) was co-local- and partly in the cytoplasm of Sertoli cells adja- ized in GH-positive cells (Fig. 3B). The other cent to the basement membrane of seminiferous anterior pituitary hormones including FSH (Fig. tubules (Fig. 1A). No variation in the localization 3C), LH, PRL, TSH and ACTH were not co-local- of ir-activin A was observed with age. This strong ized with activin A. In the pancreas, activin A immunostaining was noticeably reduced by pre- was strongly immunostained in islets of Langer- absorption of the antibody with excessive rh-activin hans. It was demonstrated that ir-activin A (Fig. A (Fig. 1B). In the ovary, ir-activin A was detected 4A) was co-localized with insulin in B cells (Fig. in the granulosa cells of mature follicle (Fig. 2A), 4B), but not with glucagon in A cells (Fig. 4C) by but not in those of immature follicles such as pri- immunostaining on adjacent sections. In the thy- mary, secondary and small Graafian follicles. roid, follicular cells, but not parafollicular cells, Ir-activin A was also detected in granulosa lutein were immunostained with anti-activin A antibody cells of the corpus luteum (Fig. 2D). However, no (Fig. 5A). The adrenal cortex was diffusely immu- significant immunostaining for activin A was ob- nostained for activin A, but the adrenal medulla served in thecal cells at any stage of follicular was not immunostained (Fig. 5C). Besides these development. endocrine tissues, ir-activin A was also detected in 378 WADA et al. Fig. 1. Localization of activin A, follistatin and inhibin a-subunit in human testis. Immunoreactivity for activin A is strongly positive in interstitial Leydig cells and in Sertoli cells adjacent to the basement membrane of the tubules in human testis (A). The specific immunostaining of activin A is noticeably reduced when antibody preabsorbed with excess rh-activin A is used (B). Immunoreactive follistatin is detectable in Leydig cells and Sertoli cells (C). Immunoreactive inhibin a-subunit is detectable in Leydig cells (D).
Load more

Recommended publications
  • Activin-A As an Intraovarian Modulator: Actions, Localization, and Regulation of the Intact Dimer in Human Ovarian Cells
    Activin-A as an intraovarian modulator: actions, localization, and regulation of the intact dimer in human ovarian cells. J Rabinovici, … , R Schwall, R B Jaffe J Clin Invest. 1992;89(5):1528-1536. https://doi.org/10.1172/JCI115745. Research Article The actions, localization, and regulation of activin in the human ovary are unknown. Therefore, the aims of this study were (a) to define the effects of recombinant activin-A and its structural homologue, inhibin-A, on mitogenesis and steroidogenesis (progesterone secretion and aromatase activity) in human preovulatory follicular cells; (b) to localize the activin-A dimer in the human ovary by immunohistochemistry; and (c) to examine regulation of intracellular activin-A production in cultured human follicular cells. In addition to stimulating mitogenic activity, activin-A causes a dose- and time-dependent inhibition of basal and gonadotropin-stimulated progesterone secretion and aromatase activity in human luteinizing follicular cells on day 2 and day 4 of culture. Inhibin-A exerts no effects on mitogenesis, basal or gonadotropin- stimulated progesterone secretion and aromatase activity, and does not alter effects observed with activin-A alone. Immunostaining for dimeric activin-A occurs in granulosa and cumulus cells of human ovarian follicles and in granulosa- lutein cells of the human corpus luteum. cAMP, and to a lesser degree human chorionic gonadotropin and follicle- stimulating hormone, but not inhibin-A, activin-A, or phorbol 12-myristate 13-acetate, increased the immunostaining for activin-A in cultured granulosa cells. These results indicate that activin-A may function as an autocrine or paracrine regulator of follicular function in the human ovary.
    [Show full text]
  • Inhibitory Effects of Activin on the Growth and Morphogenesis of Primary and Transformed Mammary Epithelial Cells'
    ICANCERRESEARCH56. I 155-I 163. March I. 19961 Inhibitory Effects of Activin on the Growth and Morphogenesis of Primary and Transformed Mammary Epithelial Cells' Qiu Yan Liu, Birunthi Niranjan, Peter Gomes, Jennifer J. Gomm, Derek Davies, R. Charles Coombes, and Lakjaya Buluwela2 Departments of Medical Oncology (Q. Y. L, P. G.. J. J. G., R. C. C., L B.J and Biochemistry (Q. Y. L. L B.J. Charing Cross and Westminster Medical School, Fuiham Palace Road. London W6 8RF; Division of Cell Biology and Experimental Pathology. Institute of Cancer Research, 15 Cotswald Rood, Sutton. Surrey SM2 SNG (B. NJ; and FACS Analysis Laboratory. imperial Cancer Research Fund, Lincoln ‘sInnFields. London WC2A 3PX (D. DI, United Kingdom ABSTRACT logical activities of activin. Indeed, two types of activin receptors have aLready been identified in the mouse (28) and several forms in Activin Is a member of the transforming growth factor fi superfamily, Xenopus (29, 30). The sequences of the Act-RI! (3 1), the TGF-@ type which is known to have activities Involved In regulating differentiation II receptor (32), the TGF-f3 type I receptor (33), and various activin and development. By using reverse transcrlption.PCR analysis on immu noafflnity.purlfied human breast cells, we have found that activin IJa and receptor-like genes (34) have been described. The comparison of these activin type II receptor are expressed by myoepithelial cells, whereas no sequences shows that they belong to a newly defined family of expression was detected In other breast cell types. In examining 15 breast membrane-bound, ligand-activated serine-threonine kinases (35).
    [Show full text]
  • Production and Purification of Recombinant Human Inhibin and Activin
    199 Production and purification of recombinant human inhibin and activin S A Pangas1 and T K Woodruff1,2 1Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA 2Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA (Requests for offprints should be addressed to T K Woodruff; Email: [email protected]) Abstract Inhibin and activin are protein hormones with diverse Conditioned cell media can be purified through column physiological roles including the regulation of pituitary chromatography resulting in dimeric mature 32–34 kDa FSH secretion. Like other members of the transforming inhibin A and 28 kDa activin A. The purified recom- growth factor- gene family, they undergo processing binant proteins maintain their biological activity as from larger precursor molecules as well as assembly into measured by traditional in vitro assays including the regu- functional dimers. Isolation of inhibin and activin from lation of FSH in rat anterior pituitary cultures and the natural sources can only produce limited quantities of regulation of promoter activity of the activin-responsive bioactive protein. To purify large-scale quantities of promoter p3TP-luc in tissue culture cells. These proteins recombinant human inhibin and activin, we have utilized will be valuable for future analysis of inhibin and activin stably transfected cell lines in self-contained bioreactors to function and have been distributed to the US National produce protein. These cells produce approximately Hormone and Peptide Program. 200 µg/ml per day total recombinant human inhibin. Journal of Endocrinology (2002) 172, 199–210 Introduction residues (Dubois et al. 2001, Leitlein et al. 2001). The subtilisin-like proprotein covertases also cleave other Inhibin is a gonadal peptide originally isolated from ovarian TGF- family members such as Mullerian-inhibiting follicular fluid (Ling et al.
    [Show full text]
  • A Study of Serum Levels of Inhibin a and B, Pro Alpha-C and Activin a in Women with Ovulatory Disturbances Before and After Stimulation with Gnrh
    European Journal of Endocrinology (2000) 143 77±84 ISSN 0804-4643 CLINICAL STUDY Inverse correlation between baseline inhibin B and FSH after stimulation with GnRH: a study of serum levels of inhibin A and B, pro alpha-C and activin A in women with ovulatory disturbances before and after stimulation with GnRH Fritz W Casper, Rudolf J Seufert1 and Kunhard Pollow Department of Experimental Endocrinology and 1Department of Obstetrics and Gynecology, Johannes Gutenberg University Mainz, D-55101 Mainz, Germany (Correspondence should be addressed to F W Casper, Department of Experimental Endocrinology, Langenbeckstrasse 1, D-55101 Mainz, Germany; Email: [email protected]) Abstract Objective: Interest has focused recently on the in¯uences of the polypeptide factors inhibin and activin on the selective regulation of the pituitary secretion of gonadotropins. Design: Measurement of the concentrations of inhibin-related proteins in relation to the changes in pituitary gonadotropin (FSH, LH) parameters, after GnRH stimulation with a bolus injection of 100 mg gonadorelin, in 19 women with ovulatory disturbances. Methods: Serum levels of inhibin A and B, activin A, and pro alpha-C were measured using sensitive ELISA kits. Results: Within 60 min after GnRH stimulation, FSH values doubled from 5 to 10 mU/ml (P < 0.001). LH increased 12-fold from 2 to 24 mU/ml (P < 0.001). Activin A showed a signi®cant decrease from 0.47 to 0.36 ng/ml (P < 0.001), whereas pro alpha-C increased from 127 to 156 pg/ml (P 0.039). The median inhibin A concentration did not show a signi®cant change between baseline and the 60 min value, whereas inhibin B was characterized by a minor, but not signi®cant, increase in the median from 168 to 179 pg/ml (P 0.408).
    [Show full text]
  • Novel Approaches to Positively Impact the Early Life Physiology, Endocrinology, and Productivity of Bulls
    Novel Approaches to Positively Impact the Early Life Physiology, Endocrinology, and Productivity of Bulls DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Bo R. Harstine, M.S. Graduate Program in Animal Sciences The Ohio State University 2016 Dissertation Committee: Dr. Michael L. Day, Advisor Mel DeJarnette Dr. Christopher Premanandan Dr. Gustavo Schuenemann Dr. Joseph Ottobre Copyrighted by Bo Randall Harstine 2016 ABSTRACT Changes to sire selection, such as the utilization of genomic evaluations, have created a desire to collect semen from superior sires as early as possible. Therefore, a series of experiments was performed in order to determine whether a novel exogenous FSH treatment hastened puberty and positively impacted postpubertal semen production in bulls. In the first experiment, angus-cross bulls received either 30 mg NIH-FSH-P1 in a 2% hyaluronic acid solution (FSH-HA, n =11) or saline (control, n = 11) every 3.5 days from 59 to 167.5 days of age. Blood was collected every 7 days to determine testosterone concentrations and at 59, 84, 94, 130, and 169 days of age to determine activin A concentrations. FSH concentrations were determined from blood collected preceding treatment every 3.5 days, as well as during three intensive collections commencing at 66, 108, and 157 days of age. Castration was performed at 170 days of age to examine testis weight, volume, diameter of seminiferous tubules, and the number of Sertoli cells per tubule cross section. Concentrations of FSH did not differ from 59 to 91 days of age, but became greater (P < 0.05) in FSH-HA than control bulls from 94 to 167.5 days.
    [Show full text]
  • Endocrinological Assessment of Toxic Effects on the Male Reproductive System in Rats Treated with 5-Fluorouracil for 2 Or 4 Weeks
    The Journal of Toxicological Sciences, 49 Vol.27, No.1, 49-56, 2002 ENDOCRINOLOGICAL ASSESSMENT OF TOXIC EFFECTS ON THE MALE REPRODUCTIVE SYSTEM IN RATS TREATED WITH 5-FLUOROURACIL FOR 2 OR 4 WEEKS Setsuko TAKIZAWA and Ikuo HORII Department of Preclinical Science, Nippon Roche K. K., Research Center, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan (Received October 25, 2001; Accepted December 11, 2001) ABSTRACT — Endocrinological assessment of male reproductive toxicity was carried out in SD-Slc male rats treated with 5-FU (0, 20, 30 mg/kg/day) orally for 2-week or 4-week term. Serum hormone levels including GnRH, FSH, LH, prolactin, total and free testosterone, inhibin B, pro-alpha C, and activin A were determined as well as histopathological examination of the reproductive organs. The 5-FU treated groups showed histopathological changes in the testis such as degeneration of seminifer- ous epithelium. An obvious decrease in serum testosterone level was observed with a reduced organ weight of the seminal vesicle and prostate. However, no significant changes were noted in serum LH or FSH levels, nor in the morphological examination of the Leydig cells. Decreased serum levels were noted in activin A and prolactin. An increased serum level was noted in GnRH and pro-alpha C whose synthesis is regulated by FSH. Serum inhibin B levels showed a tendency toward decreasing with morphological change (vac- uolation) in Sertoli cells. These results indicated that male reproductive toxicity induced by 5-FU would be augmented by decreased serum prolactin and testosterone levels as well as a decreased func- tion of Sertoli cell, in addition to the direct cytotoxic effects on germ cells.
    [Show full text]
  • Activin-A Stimulates Hypothalamic Gonadotropin-Releasing Hormone Release by the Explanted Male Rat Hypothalamus: Interaction with Inhibin and Androgens
    269 Activin-A stimulates hypothalamic gonadotropin-releasing hormone release by the explanted male rat hypothalamus: interaction with inhibin and androgens A E Calogero, N Burrello, A M Ossino, P Polosa and R D’Agata Division of Andrology, Department of Internal Medicine, University of Catania, 95123 Catania, Italy (Requests for offprints should be addressed to A E Calogero, Istituto di Medicina Interna e Specialita` Internistiche, Ospedale Garibaldi, Piazza S.M. di Gesu`, 95123 Catania, Italy) Abstract The presence of activins in those hypothalamic regions had no effect on GnRH output. As previously shown, containing gonadotropin-releasing hormone (GnRH)- testosterone (1 nmol/l) and dihydrotestosterone (DHT, secreting neurons suggests that these peptides may regulate 0·1 nmol/l) suppressed basal GnRH release, but only the reproductive function modulating not only pituitary testosterone was able to inhibit the release of GnRH FSH release and biosynthesis, but also hypothalamic stimulated by activin-A. Since DHT is a non-aromatizable GnRH release. The purpose of this study was to evaluate androgen, we evaluated whether the inhibitory effect of the effects of activin-A, a homodimer of inhibin âA testosterone was due to its in vitro conversion into 17â- subunit, on hypothalamic GnRH release in vitro and, estradiol. The addition of 4-hydroxyandrostenedione, a because of their well known antithetical effects, to evalu- steroidal aromatase inhibitor, did not influence the sup- ate its interaction with inhibin. In addition, since andro- pressive effect of testosterone on GnRH release stimulated gens modulate the release of GnRH from male rat by activin-A. hypothalami, we thought it of interest to study the possible In conclusion, activin-A stimulated hypothalamic interplay between these steroids and activin on GnRH GnRH release in vitro and this effect was abolished by release.
    [Show full text]
  • Inhibin and Activin Modulate the Release of Gonadotropin-Releasing Hormone, Human Chorionic Gonadotropin, and Progesterone From
    Proc. Nati. Acad. Sci. USA Vol. 86, pp. 5114-5117, July 1989 Medical Sciences Inhibin and activin modulate the release of gonadotropin-releasing hormone, human chorionic gonadotropin, and progesterone from cultured human placental cells (foliculostatin/follicle-stimulating hormone-releasing protein/follitropin/foliicle-stimulating hormone) FELICE PETRAGLIA*, JOAN VAUGHAN, AND WYLIE VALEt Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037 Communicated by C. H. Sawyer, March 20, 1989 (receivedfor review September 23, 1988) ABSTRACT Although it is clear that human chorionic cotropin], supports the hypothesis that placental hormono- gonadotropin (hCG) and progesterone play fundamental roles genesis may be regulated in part by locally produced peptides in pregnancy, the regulation of placental production of these (13-22). hormones remains to be defined. Recent evidence suggests that A recent report (11) showed that the addition of inhibin the human placenta expresses proteins related to inhibin (afi antiserum increased hCG production in primary human pla- subunits) or activin (8P subunits). Inhibin and activin (follicle- cental cultures, suggesting that endogenous inhibin might stimulating hormone-releasing protein) possess opposing ac- tonically inhibit secretion of the placental gonadotropin. To tivities in several biological systems including pituitary follicle- evaluate the possible roles of inhibin-related proteins in the stimulating hormone (follitropin) secretion, erythroid differ- regulation of placental hormones more directly, we have entiation, and gonadal sex-steroid production. The actions of investigated the effects-ofinhibin and activin on the secretion purified inhibin and activin on hormonogenesis by primary ofGnRH, hCG, and progesterone by cultured placental cells. cultures of human placental cells were studied.
    [Show full text]
  • Activins and Inhibins: Roles in Development, Physiology, and Disease
    Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Activins and Inhibins: Roles in Development, Physiology, and Disease Maria Namwanje1 and Chester W. Brown1,2,3 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030 2Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030 3Texas Children’s Hospital, Houston, Texas 77030 Correspondence: [email protected] Since their original discovery as regulators of follicle-stimulating hormone (FSH) secretion and erythropoiesis, the TGF-b family members activin and inhibin have been shown to participate in a variety of biological processes, from the earliest stages of embryonic devel- opment to highly specialized functions in terminally differentiated cells and tissues. Herein, we present the history, structures, signaling mechanisms, regulation, and biological process- es in which activins and inhibins participate, including several recently discovered biolog- ical activities and functional antagonists. The potential therapeutic relevance of these advances is also discussed. INTRODUCTION, HISTORY AND which the activins and inhibins participate, rep- NOMENCLATURE resenting some of the most fascinating aspects of TGF-b family biology. We will also incorporate he activins and inhibins are among the 33 new biological activities that have been recently Tmembers of the TGF-b family and were first discovered, the potential clinical relevance of described as regulators of follicle-stimulating
    [Show full text]
  • Activin Receptors in Gonadotrope Cells: New Tricks for Old Dogs
    Activin receptors in gonadotrope cells: new tricks for old dogs By Carlis Rejón G. Department of Pharmacology and Therapeutics McGill University Montréal, Canada June, 2012 A thesis submitted to McGill in partial fulfilment of the requirements of the degree of Doctor of philosophy Copyright ©Carlis Rejón G., 2012 Dedication I have had many role models during my life: Mother Teresa, a little woman with a huge spirit, who created a worldwide institution destined to assist the poorest people, regardless of their beliefs. Marie Curie an example of perseverance and dedication towards science, she was the first person to win two Nobel prizes (in Physics and Chemistry). However, my closest source of inspiration comes from a strong woman whom, with a lot of effort was able to raise four children alone. She taught me to be perseverant, honest and humble in the pursuit of my dreams. I dedicate this manuscript to her, Carmen Gonzalez, my mom. 2 Abstract Activins are members of the transforming growth factor β (TGFβ) superfamily. Though originally identified as stimulators of pituitary follicle-stimulating hormone (FSH) synthesis and secretion, they also play diverse biological roles, ranging from control of cellular differentiation to regulation of immune responses. To exert their biological effects, activins and other TGFβ family members signal through a heterotetrameric complex composed of two type I (also called activin receptor-like kinases or ALKs) and two type II transmembrane serine/threonine kinase receptors. Within the superfamily, ligands greatly outnumber receptors, hence multiple ligands share receptors and individual ligands can bind various receptors. For instance, activins bind to type II receptors ACVR2 and ACVR2B, leading to recruitment, phosphorylation, and activation of type I receptors (predominantly ALK4 for activins), which in turn phosphorylate downstream effectors.
    [Show full text]
  • Activin and Inhibin in the Human Adrenal Gland. Regulation and Differential Effects in Fetal and Adult Cells
    Activin and inhibin in the human adrenal gland. Regulation and differential effects in fetal and adult cells. S J Spencer, … , P C Goldsmith, R B Jaffe J Clin Invest. 1992;90(1):142-149. https://doi.org/10.1172/JCI115827. Research Article Recent experimental data have revealed that activins and inhibins exert pivotal effects on development. As part of our studies on growth and differentiation of the human fetal adrenal gland, we examined the subunit localization, as well as the mitogenic and steroidogenic actions of activin and inhibin in human fetal and adult adrenals. All three activin and inhibin subunit proteins (alpha, beta A, and beta B) were detected in the fetal and adult adrenal cortex. Immunoreactive activin-A dimer was demonstrated in midgestation fetal and neonatal adrenals. ACTH1-24-stimulated fetal adrenal cell expression of alpha and beta A subunit messenger RNA. In addition, ACTH elicited a rise in levels of immunoreactive alpha subunit secreted by fetal and adult adrenal cells. Human recombinant activin-A inhibited mitogenesis and enhanced ACTH-stimulated cortisol secretion by cultured fetal zone cells, but not definitive zone or adult adrenal cells. Recombinant inhibin-A had no apparent mitogenic or steroidogenic effects. Thus, activin selectively suppressed fetal zone proliferation and enhanced the ACTH-induced shift in the cortisol/dehydroepiandrosterone sulfate ratio of fetal zone steroid production. These data indicate that activin-A may be an autocrine or paracrine factor regulated by ACTH, involved in modulating growth and differentiated function of the human fetal adrenal gland. Find the latest version: https://jci.me/115827/pdf Activin and Inhibin in the Human Adrenal Gland Regulation and Differential Effects in Fetal and Adult Cells Susan J.
    [Show full text]
  • CHARACTERIZATION of the IMMUNE RESPONSE to ANTI-MÜLLERIAN HORMONE JUSTIN M. JOHNSON Bachelor of Science in Biology University O
    CHARACTERIZATION OF THE IMMUNE RESPONSE TO ANTI-MÜLLERIAN HORMONE JUSTIN M. JOHNSON Bachelor of Science in Biology University of Akron December 1994 Submitted in partial fulfillment of requirements for the degree DOCTOR OF PHILOSOPHY IN REGULATORY BIOLOGY WITH SPECIALIZATION IN CELLULAR AND MOLECULAR MEDICINE at the CLEVELAND STATE UNIVERSITY December 2020 Copyright 2020 Justin M. Johnson We hereby approve this dissertation For Justin M. Johnson Candidate for the Doctor of Regulatory Biology degree with specialization in Cellular and Molecular Medicine for the Department of Biological, Geological, and Environmental Sciences And CLEVELAND STATE UNIVERSITY'S College of Graduate Studies by __________________________________________________Date:_____________ Dr. Vincent K. Tuohy, Department of Inflammation and Immunity, Cleveland Clinic Major Advisor __________________________________________________Date:_____________ Dr. Anton Komar, Department of BGES, Cleveland State University Advisory Committee Member __________________________________________________Date:_____________ Dr. Xiaoxia Li, Department of Inflammation and Immunity, Cleveland Clinic Advisory Committee Member __________________________________________________Date:_____________ Dr. William Baldwin, Department of Inflammation and Immunity, Cleveland Clinic Advisory Committee Member __________________________________________________Date:_____________ Dr. Barsanjit Mazumder, Department of BGES, Cleveland State University Internal Examiner __________________________________________________Date:_____________ Dr. Anna Valujskikh, Department of Inflammation and Immunity, Cleveland Clinic External Examiner DEDICATION To Miss Mencl, who taught me how to put on my jacket all by myself. And to my Mom, for believing me when I pretended that I couldn’t. To Mr. Taylor, who put the idea of “Doc” in my head. And to Dr. Tuohy who made it happen. To my colleagues who encouraged me. And to my committee that inspired me. To my family and friends who motivated me to push on. And to my students who knew that I could do it.
    [Show full text]