title: The pineal gland: A model for adrenergic modulation of ubiquitin ligases.
abstract: BACKGROUND
  A recent study of the pineal gland of the rat found that the expression of more than 3000 genes showed significant day/night variations (The Hartley dataset). The investigators of this report made available a supplemental table in which they tabulated the expression of many genes that they did not discuss, including those coding for components of the ubiquitin proteasome system. Herein we identify the genes of the ubiquitin proteasome system whose expression were significantly influenced by environmental lighting in the Hartley dataset, those that were stimulated by DBcAMP in pineal glands in culture, and those that were stimulated by norepinephrine.
  
  
  OBJECTIVE
  Using the Ubiquitin and Ubiquitin-like Conjugation Database (UUCA) we identified ubiquitin ligases and conjugases, and deubiquitinases in the Hartley dataset for the purpose of determining whether expression of genes of the ubiquitin proteasome pathway were significantly influenced by day/night variations and if these variations were regulated by autonomic innervation of the pineal gland from the superior cervical ganglia.
  
  
  METHODS
  In the Hartley experiments pineal glands groups of rats sacrificed during the day and groups sacrificed during the night were examined for gene expression. Additional groups of rats had their superior cervical ganglia removed surgically or surgically decentralized and the pineal glands likewise examined for gene expression.
  
  
  RESULTS
  The genes with at least a 2-fold day/night significant difference in expression included genes for 5 ubiquitin conjugating enzymes, genes for 58 ubiquitin E3 ligases and genes for 6 deubiquitinases. A 35-fold day/night difference was noted in the expression of the gene Sik1, which codes for a protein containing both an ubiquitin binding domain (UBD) and an ubiquitin-associated (UBA) domain. Most of the significant differences in these genes were prevented by surgical removal, or disconnection, of the superior cervical ganglia, and most were responsive, in vitro, to treatment with a cyclic AMP analog, and norepinephrine. All previously described 24-hour rhythms in the pineal require an intact sympathetic input from the superior cervical ganglia.
  
  
  CONCLUSIONS
  The Hartley dataset thus provides evidence that the pineal gland is a highly useful model for studying adrenergically dependent mechanisms regulating variations in ubiquitin ligases, ubiquitin conjugases, and deubiquitinases, mechanisms that may be physiologically relevant not only in the pineal gland, but in all adrenergically innervated tissue.
authors.affiliation: Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Jerry
authors.identifier: http://orcid.org/0000-0001-6435-755X
authors.initials: J
authors.lastname: Vriend
authors.affiliation: Department of Pathology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, Texas, United States of America.
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
mesh_terms: D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002940:Circadian Rhythm / Q000235:genetics; D000072017:Deubiquitinating Enzymes / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D008550:Melatonin / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D010870:Pineal Gland / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D044094:Receptors, Melatonin / Q000378:metabolism; D017783:Superior Cervical Ganglion / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D003994:Bucladesine; D000072017:Deubiquitinating Enzymes; D007453:Iodide Peroxidase; D008550:Melatonin; D009638:Norepinephrine; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D044094:Receptors, Melatonin; D044767:Ubiquitin-Protein Ligases; D000097564:Iodothyronine Deiodinase Type II; C120299:Sik1 protein, rat