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 without ligand treatment is very limited. Our data suggested a strong likelihood that autophagy is responsible for the AHR protein degradation in human cells. In this grant proposal, we will investigate whether and how autophagy regulates the AHR protein levels in human cells. In brief, we will perform experiments to study the following aims: (1) we will determine whether the autophagy-mediated AHR protein degradation occurs in cancerous and normal human cells (Aim 1); we will determine the autophagy mechanism that is involved in the AHR degradation (Aim 2) and (3) we will investigate how triple-negative human breast cancer cells are more sensitive in the autophagy- mediated AHR protein degradation when compared to non-triple-negative breast cancer cells (Aim 3).
Function of the aryl hydrocarbon receptor is essential in response to environmental pollutants and normal cellular processes. We are interested in the regulatory mechanisms which control the aryl hydrocarbon receptor protein levels in human cells. This grant proposal focuses on how the aryl hydrocarbon receptor protein is degraded via autophagy without ligand treatment in humans.
| Pappas, Beverly; Yang, Yujie; Wang, Yu et al. (2018) p23 protects the human aryl hydrocarbon receptor from degradation via a heat shock protein 90-independent mechanism. Biochem Pharmacol 152:34-44 |
| Ren, Lina; Thompson, John D; Cheung, Michael et al. (2016) Selective suppression of the human aryl hydrocarbon receptor function can be mediated through binding interference at the C-terminal half of the receptor. Biochem Pharmacol 107:91-100 |
| Zheng, Yujuan; Xie, Jinghang; Huang, Xin et al. (2016) Binding studies using Pichia pastoris expressed human aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator proteins. Protein Expr Purif 122:72-81 |
