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UT Biological Sciences Faculty Research - Dr. Lirim Shemshedini

Lirim Shemshedini

 

Lirim Shemshedini

Professor
Ph.D., University of Vermont, 1989

Office:         WO 3227    
Phone No:  419.530.1553
Email:         lirim.shemshedini@utoledo.edu 

 

 

 

 

 

 

Research

Dr. Shemshedini's Research GroupMy lab studies the role of androgen receptor (AR) in prostate cancer.  One part of this work has focused on proteins regulating the activity of AR and this led to the identification AP-1 components and p53 as important regulators of AR activity.  Our lab was the first lab to demonstrate that c-Jun acts as a coactivator for AR and is an important mediator of AR regulation of genes and cell proliferation.  We also were the first to identify a novel activity for p53, that of a repressor of AR transcriptional activity.  Indeed, we showed that c-Jun and p53 antagonize each other’s activity on AR, with c-Jun promoting AR dimerization and DNA binding and p53 inhibiting both processes.  Our studies with c-Jun activity on AR led us to the second major part of our group’s research efforts, the identification of novel AR-regulated genes. Among these was sGCα1, a gene encoding a subunit of sGC (Soluble Guanylyl Cyclase), the receptor for nitric oxide (NO) catalyzing cGMP synthesis. Our data showed for the first time that sGCα1 has promoting functions in prostate cancer independent of NO signaling. Indeed, we clearly showed that sGCα1 over-expression was sufficient to promote the growth and survival of prostate cancer cells that is observed in the presence of androgen, making sGCα1 a key androgen-regulated gene in prostate cancer. In view of this, our lab has generated a number of peptides that target sGCα1 and kill prostate cancer cells. Indeed, these peptides provide a new paradigm for prostate cancer therapy.  In addition, we published a novel function of sGCα1, that of inhibiting p53 activity, and thus providing the prostate cancer and increased ability to evade p53-dependent apoptosis.  This work led our lab to discover of new protein complex, consisting of sGCα1, p53, Casein Kinase 2, and components of the COP9 Signalosome, which has pro-growth and pro-survival functions in prostate cancer.  Finally, we identified the gene encoding the transmembrane protein TM4SF3, also known as Tetraspanin 8, as novel androgen-regulated gene. Interestingly, our studies determined that this transmembrane protein also exhibits a nuclear localization in prostate cancer cells, and associates with AR to form a mutually stabilizing complex. This represents the identification of a novel AR-interacting protein that is important for AR protein stability in prostate cancer.

Current students

Jun Zhou
Mamata Malla
Jacob Brandman
Amanda Weddington

Current laboratory grants

University of Toledo Biomedical Research Innovation Grant

Publications

1. Bhansali M, Zhou J, Shemshedini L. TM4SF3 and AR: A Nuclear Complex that Stabilizes Both Proteins. Mol Endocrinol. 2016 Jan;30(1):13-25. doi: 10.1210/me.2015-1075. Epub 2015 Dec 9

2. Bhansali M, Shemshedini L. (2014) COP9 Subunits 4 and 5 Target Soluble Guanylyl Cyclase α1 and p53 in Prostate Cancer Cells. Mol Endocrinol. 2014 Jun;28(6):834-45. doi: 10.1210/me.2014-1017. Epub 2014 Apr 11. (PMID: 24725084)

3. Gao, S., Hsieh, C.L., Zhou, J., Shemshedini, L. (2013) Zinc Finger 280B Down-Regulates p53 by Inducing Mdm2 Expression in Prostate Cancer Cells. PLoS One. 8(11):e78766. (PMID: 24236047)

4. Gao, S., Hsieh, C.L., Bhansali, M., Kannan, A., Shemshedini, L. (2013) A Peptide against soluble guanylyl cyclase α1: a new approach to treating prostate cancer. PLoS One. 27;8(5):e64189.
(PMID: 23724033)

5. Cai, C, Hsieh, C-L., Gao, S., Kannan, A., Bhansali, M., Govardhan, K., and Shemshedini, L. (2012) Soluble guanylyl cyclase α1 and p53 cytoplasmic sequestration and down-regulation in prostate cancer. Mol. Endocr. 26, 292-307. (PMID: 22174378)

6. Periyasamy, S., Hinds, T Jr., Shemshedini, L., Shou, W., Sanchez, ER. (2010) FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A. Oncogene 29, 1691-1701. (PMID: 20023700)

7. Zhang, J., Gonit, M., Salazar, M.D., Shatnawi, A., Shemshedini, L., Trumbly, R., Ratnam, M. (2010) C/EBPalpha redirects androgen receptor signaling through a unique bimodal interaction. Oncogene 29, 723-738. (PMID: 19901962)

8. Shemshedini, L. (2009) Use of reporter genes to study promoters of the androgen receptor. Methods Mol Biol. 590, 195-207. (PMID: 19763505)

9. Hsieh, C-L., Cai, C, Giwa, A., Bivins, A., Chen, S-Y., Sabry, D., Govardhan, K., and Shemshedini, L. (2007) Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells. J. Mol. Endocr. 41, 13-23. (PMID: 18469090)

10. Cai, C, Hsieh, C-L., and Shemshedini, L. (2007) c-Jun has multiple enhancing activities in the novel cross-talk between the androgen receptor and ETV1 in prostate cancer cells. Mol. Canc. Res. 5, 725-735. (PMID: 17634427)
11. Cai, C, Hsieh, C-L., Omwacha, J., Zheng, Z., Chen, S-Y., Baert, J-L., and Shemshedini, L. (2007) ETV1 is a novel androgen receptor-regulated gene that mediates prostate cancer cell invasion. Mol. Endocr. 21, 1835-1846. (PMID: 17505060)

12. Cai, C., Omwancha, J., Hsieh, C-L., and Shemshedini, L. (2007) Androgen induces expression of the multidrug resistance protein gene MRP4 in prostate cancer cells. Prostate Cancer and Prostatic Diseases 10:39-45. Epub Sept. 26. (PMID: 17003774)

13. Cai, C., Chen, S.Y., Zheng, Z., Omwancha, J., Lin, M-F., Balk, S.P., Shemshedini, L. (2007) Androgen regulation of soluble guanylyl cylase α1 mediates prostate cancer cell proliferation. Oncogene 26, 1606-1615. Epub Sept. 11. (PMID: 16964290)

Last Updated: 10/10/16