Transcriptional regulation of the human P450 oxidoreductase gene: hormonal regulation and influence of promoter polymorphisms

Molecular Endocrinology
Meng Kian TeeWalter L Miller

Abstract

P450 oxidoreductase (POR) is the flavoprotein that acts as the obligatory electron donor to all microsomal P450 enzymes, including those involved in hepatic drug metabolism as well as three steroidogenic P450 enzymes. The untranslated first exon of human POR was located recently, permitting analysis of human POR transcription. Expression of deletional mutants containing up to 3193 bp of the human POR promoter in human adrenal NCI-H295A and liver Hep-G2 cells located the proximal promoter at -325/-1 bp from the untranslated exon. Common human POR polymorphisms at -208 and -173 had little influence on transcription, but the polymorphism at -152 reduced transcription significantly in both cell lines. EMSA and supershift assays identified binding of Smad3/Smad4 between -249 and -261 and binding of thyroid hormone receptor-β (TRβ) at -240/-245. Chromatin immunoprecipitation showed that Smad3, Smad4, TRα, TRβ, and estrogen receptor-α were bound between -374 and -149. Cotransfection of vectors for these transcription factors and POR promoter-reporter constructs into both cell types followed by hormonal treatment showed that T(3) exerts major tropic effects via TRβ, with TRα, estrogen receptor-α, Smad3, and Smad4 exerting lesser, modul...Continue Reading

References

Dec 15, 1975·European Journal of Biochemistry·F ZuninoA Zaccara
Dec 18, 1986·Nature·C WeinbergerR M Evans
Apr 30, 1985·Biochemical and Biophysical Research Communications·A DeeM R Waterman
Aug 1, 1995·The Journal of Steroid Biochemistry and Molecular Biology·A EndohY Igarashi
Dec 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·I JohanssonMagnus Ingelman-Sundberg
May 1, 1994·Archives of Biochemistry and Biophysics·K A O'LearyC B Kasper
Aug 5, 1997·Proceedings of the National Academy of Sciences of the United States of America·M WangJ J Kim
Jun 23, 2000·Archives of Biochemistry and Biophysics·K A O'Leary, C B Kasper
Aug 8, 2002·Thyroid : Official Journal of the American Thyroid Association·Clare B Harvey, Graham R Williams
Apr 3, 2004·Genome Research·Diana KolbeFrancesca Chiaromonte
Jun 25, 2004·Nucleic Acids Research·Gabriela G Loots, Ivan Ovcharenko
Jul 21, 2004·American Journal of Medical Genetics. Part a·Masanori AdachiAkira Oka
Nov 5, 2004·Journal of Molecular Endocrinology·Kwang-Huei LinChia-Siu Wang
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Mar 29, 2007·The Journal of Clinical Endocrinology and Metabolism·Rachel R ScottWalter L Miller
Jun 20, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Alison E Aitken, Edward T Morgan
Jan 31, 2008·Proceedings of the National Academy of Sciences of the United States of America·Ningwu HuangWalter L Miller
Jun 19, 2008·The Journal of Clinical Endocrinology and Metabolism·Eli HershkovitzWalter L Miller

Citations

Jan 18, 2013·Pharmacogenetics and Genomics·Laure ElensRon H N van Schaik
May 13, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Xiuling ZhangLaurence S Kaminsky
Jun 4, 2013·Experimental and Toxicologic Pathology : Official Journal of the Gesellschaft Für Toxikologische Pathologie·Gabriela MazzantiAnnabella Vitalone
Jan 29, 2013·Pharmacology & Therapeutics·Amit V Pandey, Christa E Flück
Jun 3, 2014·Pharmacology & Therapeutics·Payman ShahabiSophie Visvikis-Siest
Nov 13, 2010·Molecular and Cellular Endocrinology·Walter L MillerKathleen M Giacomini
Aug 17, 2011·Biochemical and Biophysical Research Communications·Christa E FlückAmit V Pandey

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Hereditary Sensory Autonomic Neuropathy

Hereditary Sensory Autonomic Neuropathies are a group of inherited neurodegenerative disorders characterized clinically by loss of sensation and autonomic dysfunction. Here is the latest research on these neuropathies.

Spatio-Temporal Regulation of DNA Repair

DNA repair is a complex process regulated by several different classes of enzymes, including ligases, endonucleases, and polymerases. This feed focuses on the spatial and temporal regulation that accompanies DNA damage signaling and repair enzymes and processes.

Glut1 Deficiency

Glut1 deficiency, an autosomal dominant, genetic metabolic disorder associated with a deficiency of GLUT1, the protein that transports glucose across the blood brain barrier, is characterized by mental and motor developmental delays and infantile seizures. Follow the latest research on Glut1 deficiency with this feed.

Separation Anxiety

Separation anxiety is a type of anxiety disorder that involves excessive distress and anxiety with separation. This may include separation from places or people to which they have a strong emotional connection with. It often affects children more than adults. Here is the latest research on separation anxiety.

KIF1A Associated Neurological Disorder

KIF1A associated neurological disorder (KAND) is a rare neurodegenerative condition caused by mutations in the KIF1A gene. KAND may present with a wide range and severity of symptoms including stiff or weak leg muscles, low muscle tone, a lack of muscle coordination and balance, and intellectual disability. Find the latest research on KAND here.

Regulation of Vocal-Motor Plasticity

Dopaminergic projections to the basal ganglia and nucleus accumbens shape the learning and plasticity of motivated behaviors across species including the regulation of vocal-motor plasticity and performance in songbirds. Discover the latest research on the regulation of vocal-motor plasticity here.