- Collection:
- Atlanta University and Clark Atlanta University Theses and Dissertations
- Title:
- ID4 protein regulates FKBP52 and β-catenin interaction reducing the AR downstream signaling in CRPC
- Creator:
- Al-Zahrani, Majid
- Date of Original:
- 2020-07
- Subject:
- Degrees, Academic
Dissertations, Academic - Location:
- United States, Georgia, Fulton County, Atlanta, 33.749, -84.38798
- Medium:
- theses
dissertations - Type:
- Text
- Format:
- application/pdf
- Description:
- The inhibitor of DNA binding protein 4 (ID4) is a basic helix-loop-helix (bHLH) dominant negative regulator of other transcription factors. ID4 acts as a tumor suppressor in the prostate and the loss of ID4 is associated with prostate cancer tumorigenesis resulting in a constitutive activation of androgen receptor (AR) leading to castration-resistant prostate cancer (CRPC). The molecular mechanisms by which ID4 is downregulated and AR is activated is still elusive and require more investigations. We previously demonstrated that the loss of ID4 increased the levels of some chaperone proteins such as Heat shock protein 27 (Hsp27) and FK506-binding protein 52 (FKBP52), which are involved in activating co-localizing AR into the nucleus to activate AR pathway. Moreover, our genomic and proteomic data showed a significant increase in β-catenin levels in LNCaP(-)ID4 cells due to the loss of ID4. The co-immuno-precipitation (co-IP) data shows that ID4 expression in LNCaP cells blocked the protein interaction between AR-FKBP52-β-catenin by binding to FKBP52 and the loss of ID4 promoted the interaction suggesting that ID4 disrupted the interaction when binding to FKBP52, which is a mediator for activating AR by β-catenin. Thus, our hypothesis is that ID4 acts as a tumor suppressor by selectively regulating AR-β-catenin activity through FKBP52. Therefore, the objective of this study is to inhibit FKBP52 by targeting the proline-rich-loop on the FK1 domain to block the protein-protein interaction between AR and β-catenin to prevent AR synergistic co-activation by β-catenin and FKBP52. An FKBP52 inhibitor (GMC1) was tested in this study in-vitro and in-vivo on CRPC models (LNCaP(-)ID4 and 22RV1 cells) and our results have confirmed that GMC1 managed to reduce AR nuclear localization in LNCaP and 22RV1 cells. Also, the co-IP data confirmed that GMC1 managed to block the protein-protein interaction between AR, β-catenin, and FKBP52. Moreover, GMC1 significantly reduced the proliferation rate of LNCaP and 22RV1 cells at higher concentration (75-100µM) and attenuated the tumor growth by reducing the volume and the size for LNCaP(-)ID4 and 22RV1 xenograft tumors. Also, the immunohistological analysis results have confirmed that GMC1 affected AR, PSA, Ki67, and FKBP51 expression xenograft tissue samples.
Date of award: 2020-07
Degree type: dissertation
Degree name: Doctor of Philosophy (PhD)
Granting institution: Clark Atlanta University
Department: Department of Biological Sciences
Advisor: Chaudhary, Jaideep - Metadata URL:
- http://hdl.handle.net/20.500.12322/cau.td:2020_alzahrani_majid
- Holding Institution:
- Atlanta University Center Robert W. Woodruff Library
- Rights:
-
