Investigating the molecular mechanisms in controlling the aryl hydrocarbon recept

University Of The Pacific-Stockton, Stockton CA

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Abstract

DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AhR) is a ligand-activated basic-helix-loop-helix-PAS transcription factor. This receptor is responsible for our bodily response to exposure of environmental pollutants such as polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and dioxins. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most studied and best known ligand of AhR. Expression of AhR is up-regulated in human cancers and during T cell differentiation. Malfunction of the events affecting the AhR gene expression would undoubtedly cause problems in cancer, aberrant immune response, stem cell development, and our response to toxic environmental chemicals. However, our knowledge of how the AhR protein levels are maintained in the absence of ligand is very limited. Recently, we generated p23-knockdown stable cells and discovered that compromised p23 levels in human hepatoma (Hep3B) and cervical (HeLa) cells suppress the AhR protein levels by reducing its protein degradation in the absence of ligand. In this grant proposal, we wil ultilize these stable cells to investigate the molecular mechanisms that regulate the human AhR protein levels in the absence of ligand. Specifically, we will perform the following experiments: (1) investigate whether conformation of the unliganded AhR complex governs the AhR protein stability (Aim 1) and (2) investigate whether and how p23 acts locally at the AhR complex level to control AhR protein stability (Aim 2) and (3) investigate the involvement of non-proteasomal degradation mechanisms and identify and characterize new protein target(s) which are responsible for controlling the human AhR protein degradation (Aim 3).