Ah Receptor Anatomy: Implications for Dioxin Toxicity

Summary

Principal Investigator: CORNELIS JOHAN ELFERINK
Abstract: Toxins, pathogenic infection (viral and bacterial), and physical injury to the liver results in a loss of hepatic tis- ue, triggering a regenerative response to restore liver cell mass. Dysregulation in the repair process can lead o liver failure or liver cancer. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor Imctionally identified with proliferative processes. TheAhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) he prototype for a class of compounds responsible for a range of toxic or adaptive endpoints, inhibits liver re- generation following tissue injury thus implicating the AhR in liver repair. Our long-term goal is to understand Tiechanistically how the AhR contributes to liver homeostasis by regulating cell proliferation, and thereby identify he molecular basis for TCDD-induced disruption of normal biological processes. We hypothesize that the AhR plays an important role in liver homeostasis, in part by regulating progress through G1phase of the cell cycle l/n proliferating hepatocytes. The goal of this proposal is to examine the functional relationship between AhR activity and TCDD responsiveness proteins known to regulate hepatocyte proliferation. Specifically, the planned studies will examine the molecular basis and relative contribution of cyclin-dependent kinase 2 (CDK2) inhibi- ion and plasminogen activator inhibitor-1 (PAI-1) expression on liver regeneration. TCDD alters CDK2 activity and PAI-1 expression during liver regeneration, representing distinct intracellular and extracellular (autocrine or paracrine) mechanisms of action that conspire to inhibit the restorative response to injury. Preliminary evidence also demonstrates that AhR regulation of the PAI-1 gene involves a novel (non-XRE) DNA element that will be characterized in detail. The proposed studies are an extension of currently funded research looking at the AhR n regulating hepatic proliferation in cell culture models, and seeks to build on previous findings using a physi- ologically relevant (non-transformed) model of cell proliferation. Parallels between humans and mice in the re- generative response, instills confidence that findings generated during these studies will be directly applicable to the human condition.
Funding Period: ----------------1996 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Sustained aryl hydrocarbon receptor activity attenuates liver regeneration
    Kristen A Mitchell
    301 University Boulevard, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555 1031, USA
    Mol Pharmacol 70:163-70. 2006
  2. ncbi Scanning cytometry with a LEAP: laser-enabled analysis and processing of live cells in situ
    Peter Szaniszlo
    Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, USA
    Cytometry A 69:641-51. 2006
  3. pmc The tumor suppressor Kruppel-like factor 6 is a novel aryl hydrocarbon receptor DNA binding partner
    Shelly R Wilson
    Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, USA
    J Pharmacol Exp Ther 345:419-29. 2013
  4. pmc Biomarker discovery for early detection of hepatocellular carcinoma in hepatitis C-infected patients
    Mehnaz G Mustafa
    Departments of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555
    Mol Cell Proteomics 12:3640-52. 2013
  5. pmc Ah receptor-mediated suppression of liver regeneration through NC-XRE-driven p21Cip1 expression
    Daniel P Jackson
    Department of Pharmacology and Toxicology D P J, A D J, C J E and Department of Pediatrics H L, University of Texas Medical Branch, Galveston, Texas and Department of Biological Sciences, Boise State University, Boise, Idaho K A M
    Mol Pharmacol 85:533-41. 2014
  6. pmc Timing is everything: consequences of transient and sustained AhR activity
    Kristen A Mitchell
    Department of Pharmacology and Toxicology, and Sealy Center for Cancer Cell Biology, School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555 1031, USA
    Biochem Pharmacol 77:947-56. 2009
  7. pmc The activated aryl hydrocarbon receptor synergizes mitogen-induced murine liver hyperplasia
    Kristen A Mitchell
    Department of Pharmacology and Toxicology, School of Medicine, University of Texas Medical Branch, Galveston, TX 77555 1031, USA
    Toxicology 276:103-9. 2010
  8. pmc A novel nonconsensus xenobiotic response element capable of mediating aryl hydrocarbon receptor-dependent gene expression
    Gengming Huang
    Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555 0654, USA
    Mol Pharmacol 81:338-47. 2012

Detail Information

Publications8

  1. ncbi Sustained aryl hydrocarbon receptor activity attenuates liver regeneration
    Kristen A Mitchell
    301 University Boulevard, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555 1031, USA
    Mol Pharmacol 70:163-70. 2006
    ..These findings establish a functional role for the AhR in regulating normal cell cycle control during liver regeneration...
  2. ncbi Scanning cytometry with a LEAP: laser-enabled analysis and processing of live cells in situ
    Peter Szaniszlo
    Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, USA
    Cytometry A 69:641-51. 2006
    ..A new technology, called LEAP (laser-enabled analysis and processing), offers a unique combination of capabilities in cell purification and selective macromolecule delivery (optoinjection)...
  3. pmc The tumor suppressor Kruppel-like factor 6 is a novel aryl hydrocarbon receptor DNA binding partner
    Shelly R Wilson
    Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, USA
    J Pharmacol Exp Ther 345:419-29. 2013
    ..Collectively, the results unmask a novel AhR signaling mechanism distinct from the canonical XRE-driven process that will enrich our future understanding of AhR biology...
  4. pmc Biomarker discovery for early detection of hepatocellular carcinoma in hepatitis C-infected patients
    Mehnaz G Mustafa
    Departments of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555
    Mol Cell Proteomics 12:3640-52. 2013
    ..Future multiplexing of SRM assays for other candidate biomarkers is envisioned to develop a biomarker panel for subsequent verification and validation studies. ..
  5. pmc Ah receptor-mediated suppression of liver regeneration through NC-XRE-driven p21Cip1 expression
    Daniel P Jackson
    Department of Pharmacology and Toxicology D P J, A D J, C J E and Department of Pediatrics H L, University of Texas Medical Branch, Galveston, Texas and Department of Biological Sciences, Boise State University, Boise, Idaho K A M
    Mol Pharmacol 85:533-41. 2014
    ..The evidence also suggests that AhR functionality following partial hepatectomy is dependent on a p21(Cip1)-regulated signaling process, intimately linking AhR biology to the G1-phase cell cycle program. ..
  6. pmc Timing is everything: consequences of transient and sustained AhR activity
    Kristen A Mitchell
    Department of Pharmacology and Toxicology, and Sealy Center for Cancer Cell Biology, School of Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555 1031, USA
    Biochem Pharmacol 77:947-56. 2009
    ..The growing recognition that AhR action functions through multiple mechanisms serves to further highlight the importance of limiting prolonged receptor activation...
  7. pmc The activated aryl hydrocarbon receptor synergizes mitogen-induced murine liver hyperplasia
    Kristen A Mitchell
    Department of Pharmacology and Toxicology, School of Medicine, University of Texas Medical Branch, Galveston, TX 77555 1031, USA
    Toxicology 276:103-9. 2010
    ..These findings are in stark contrast to previous observations that the activated AhR can suppress hepatocyte proliferation in vivo and reveal a new complexity to AhR-mediated cell cycle control...
  8. pmc A novel nonconsensus xenobiotic response element capable of mediating aryl hydrocarbon receptor-dependent gene expression
    Gengming Huang
    Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555 0654, USA
    Mol Pharmacol 81:338-47. 2012
    ....