PROFILING THE EXPRESSION OF AMINO ACID TRANSPORTERS WITHIN THE CONTEXT OF THE ARYL HYDROCARBON RECEPTOR

Open Access
Author:
Lucas, Joseph H
Area of Honors:
Toxicology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Gary H Perdew, Thesis Supervisor
  • Curtis John Omiecinski, Honors Advisor
Keywords:
  • AHR
  • aryl hydrocarbon receptor
  • amino acid transporters
  • LAT1
  • OSC-19
  • jejunum
Abstract:
The aryl hydrocarbon receptor (AHR) is a transcription factor of the basic helix-loop-helix-PER-ARNT-SIM superfamily. Exogenous and endogenous ligands for the AHR mediate an array of physiologic and toxicological functions. This research hopes to identify the role of AHR dependent gene regulation on amino acid homeostasis which involves amino acid metabolism and transport. This equilibrium is usually perturbed in certain tumors, where elevated expression of transporters increases the flux of amino acids in order to supply proliferative cells and examining the relationship between AHR and amino acid homeostasis could give insights into the carcinogenic mechanism of AHR ligands as well as identify potential therapeutic targets. Quantitative real-time PCR showed that OSC-19 cells exposed to TCDD exhibited increased expression of SLC7A5/SLC3A2. These transporters were further expressed when cultured under amino acid deficiency (10%). Significant increased expression of SLC16A14, a monocarboxylic acid transporter was also observed within the amino acid deficient cells. Furthermore, AHR does not appear to affect expression of tRNA synthases (GARS, QARS, and WARS) or amino acid sensing (GCN2/ATF4) genes. Mouse jejunum samples were also used to examine the extent with which broccoli derived glucobrassicins mediated AHR induced transporter expression. Surprisingly, SLC7A5/SLC3A2 expression was not significantly altered compared to control mice. Downregulation of SLC43A3, a purine nucleobase transporter was also observed which could potentially offer some protective effect against carcinogenesis in the gut. However, there is not enough evidence to conclude that relationship exist and the data indicates that amino acid transporters in the small intestine are not susceptible to AHR regulation.