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Exploring the Roles of TM4SF3 and CSN4 in Prostate Cancer

Bhansali, Meenakshi
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1408699883

Abstract Details

2014, Doctor of Philosophy, University of Toledo, Biology (Cell-Molecular Biology).
Prostate cancer (PCa) is the most common non-skin cancer in males in the United States. Androgen Receptor (AR) is believed to remain active during progression of castration resistant PCa (CRPC). We performed gene microarray analysis and identified sGCa1 as an androgen-induced gene while TM4SF3 and BARD1 were repressed genes. Earlier we published that sGCa1 is involved in PCa cell growth and survival, independent of the classical nitric oxide (NO) signaling pathway and its association with sGCß1. We identified by mass spectrometric analysis CSN4 as a novel binding partner for sGCa1. We observed that sGCa1 and CSN4 interact and co-localize in PCa cells. CSN4 positively regulates the sGCa1 protein stability by preventing sGCa1 proteasome-dependent degradation. Furthermore, disruption of CSN4 led to reduced PCa cell growth and these cells can be rescued significantly but not entirely by overexpression of sGCa1. This observation opened the possibility of another target for CSN4, which is p53. We observed that CSN4 negatively regulates p53 protein stability by promoting its proteasome-dependent degradation. Most importantly, CSN4 knock-down cells were rescued almost completely when we overexpressed sGCa1 and p53 knock-down. CSN5 acts downstream of CSN4 and is involved in mediating the CSN4-dependent effect on sGCa1 and p53 proteins. Further, we found that CK2 kinase exists in sGCa1-p53-CSN4- CSN5 protein complex and is involved in influencing the stability of sGCa1 and p53. TM4SF3 is unique in its androgen regulation as the mRNA is androgen-repressed and protein is androgen up-regulated. We focused on androgen up-regulation of TM4SF3 in different PCa cell lines. Androgen positively regulates TM4SF3 protein stability by preventing the proteasomal-degradation of TM4SF3. Our findings demonstrate that TM4SF3 is required for migration/invasiveness and epithelial mesenchymal transition of PCa cells. In addition to being localized in the membrane, TM4SF3 exhibits a novel androgen-dependent nuclear localization in AR-positive PCa cells. Interestingly endogenous TM4SF3 interacts with nuclear AR in an androgen-dependent manner in PCa cells and in vitro. Most importantly, the association of TM4SF3 with AR is required for AR protein stability, transactivation and androgen-induced proliferation of PCa cells. TM4SF3 and AR are overexpressed in prostate tumors, consistent with their mutual stabilization in PCa cells. Like TM4SF3, BARD1 is androgen-repressed gene, downregulated at the mRNA and protein levels in PCa cells. Most importantly, overexpression of BARD1 affects endogenous AR protein levels, its transcriptional activity and endogenous gene prostate specific antigen.
Lirim Shemshedini (Committee Chair)
Scott Leisner (Committee Member)
Malathi Krishnamurthy (Committee Member)
Paul Erhardt (Committee Member)
Jeffrey Sarver (Committee Member)
215 p.
Biology; Molecular Biology
prostate cancer, sGCa1, TM4SF3, CSN4, BARD1, AR, p53, COP9 signalosome

Recommended Citations

Citations

  • Bhansali, M. (2014). Exploring the Roles of TM4SF3 and CSN4 in Prostate Cancer [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1408699883

    APA Style (7th edition)

  • Bhansali, Meenakshi. Exploring the Roles of TM4SF3 and CSN4 in Prostate Cancer. 2014. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1408699883.

    MLA Style (8th edition)

  • Bhansali, Meenakshi. "Exploring the Roles of TM4SF3 and CSN4 in Prostate Cancer." Doctoral dissertation, University of Toledo, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1408699883

    Chicago Manual of Style (17th edition)

toledo1408699883
423
© 2014, all rights reserved.
This open access ETD is published by University of Toledo and OhioLINK.