ACTH INDUCTION OF CYTOCHROME P450 IN ADRENAL CELLS

Summary

Principal Investigator: MICHAEL R contact WATERMAN
Abstract: The chronic action of ACTH maintains optimal steroidogenic capacity in the adrenal cortex, assuring production of adrenal steroid hormones (cortisol, corticosterone and aldosterone) on demand. This process is mediated by cAMP exerting transcriptional pressure on genes encoding adrenocortical steroid hydroxylases (P450s) and related proteins. This competitive renewal proposes to determine how four homeodomain proteins binding to the predominant cAMP response sequence (CRS1) of bovine CYP17 (P450c17) interact with one another and the basal transcription machinery. Using in vitro transcription/translation, EMSA, cell transfection, in vitro transcription and mutagenesis; dimerization and transactivation domains in these homeodomain proteins will be identified along with coactivators and/or TAFs with which they interact. Adrenodoxin supports activity of mitochondrial P450s in the adrenal cortex and most other tissues. The gene encoding this 2Fe-2S protein is also regulated transcriptionally by ACTH(cAMP) and the novel protein binding to this CRS will be characterized in the same manner as CYP17 CRS1 binding proteins. This will permit comparison of cAMP-dependent transcriptional regulation of a gene predominantly expressed in steroidogenic cells (CYP17) with one expressed in both steroidogenic and nonsteroidogenic cells. The signalling pathway required for exertion of transcriptional pressure by ACTH of steroidogenic genes is cAMP- responsive and inhibited by cycloheximide (CHX). The cAMP-responsive/ CHX-sensitive locus will be identified as a means of understanding this signalling pathway. The proposed studies will establish for the first time at the biochemical level how peptide hormones from the anterior pituitary control levels of steroidogenic enzymes as well as providing detailed insight into the signalling pathway required for this process. These events are required for the biosynthesis of steroid hormones leading to reproductive capacity and metabolic homeostasis.
Funding Period: 1992-07-18 - 2004-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Tetracycline protects myocardium against ischemic injury
    Norio Kagawa
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37252 0146, USA
    Front Biosci 10:608-19. 2005
  2. ncbi Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension
    James V Gainer
    Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical School, Nashville, Tenn 37232 0146, USA
    Circulation 111:63-9. 2005

Scientific Experts

  • Norio Kagawa
  • James V Gainer
  • Michael R Waterman
  • Sarah W Grant
  • L Adrienne Cupples
  • Nancy J Brown
  • Elliott P Dawson
  • Kristie E Womble
  • Chao Yu Guo
  • Aouatef Bellamine
  • Jorge H Capdevila
  • Serkalem Demissie
  • Yarong Wang
  • Christopher J O'Donnell

Detail Information

Publications2

  1. ncbi Tetracycline protects myocardium against ischemic injury
    Norio Kagawa
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37252 0146, USA
    Front Biosci 10:608-19. 2005
    ..This study is also important for providing new insights into the non-antimicrobial effects of tetracycline and its derivatives...
  2. ncbi Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension
    James V Gainer
    Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical School, Nashville, Tenn 37232 0146, USA
    Circulation 111:63-9. 2005
    ..We combined molecular and biochemical approaches to identify a functional variant of the CYP4A11 20-HETE synthase and determine its association with hypertensive status in 2 independent human populations...