The University of Toledo

UT Biological Sciences Faculty Research - Dr. Lirim Shemshedini

 

Lirim Shemshedini

Professor
Ph.D., University of Vermont, 1989

 

 

 

Research

The growth and progression of prostate cancer are dependent on androgens and the androgen receptor (AR). Androgens and AR act in cells by modulating gene expression. Our lab has two major research interests: i) proteins that regulate AR transcriptional activity and ii) AR-regulated gene expression. On the first interest, we have studied for many years the role of the proto-oncoprotein c-Jun as a coactivator of AR. Our data show that c-Jun coactivation regulates androgen-dependent proliferation of and androgen-induced gene expression in prostate cancer cells. Indeed, the growth of both androgen-dependent and –independent prostate cancer cells is compromised by down-regulation of c-Jun activity. In addition, our lab has studied the inhibitory activities on AR of c-Fos, the dimerization partner of c-Jun, and p53, a tumor suppressor that is a common target of mutational disruption in cancer. More recently, we have analyzed the role of sumoylation in regulating AR activity. These studies led to the discovery that SUMO-3, a protein that is conjugated to target proteins by sumoylation, can strongly enhance AR transcriptional activity independent of its sumoylation function.

With respect to the second research interest, we have identified several novel androgen-regulated genes through gene expression profiling studies in LNCaP cells, which are sensitive to the pro-carcinogenic effects of androgens. Among several genes that we are currently studying, our major focus is on two genes, sGC1 and ETV1. sGC1 is a component of soluble guanylyl cyclase (sGC), the enzyme that mediates the widespread cellular effects of the important signaling molecule nitric oxide (NO). Our data show that sGC1 expression increases substantially with increasing stage of prostate cancer and that sGC1 mediates androgen-dependent and androgen–independent prostate cancer cell proliferation. More evidence strongly suggests that sGC1 is having this proliferative effect independent of sGC1, NO, and cGMP, and PKG, opening the possibility of a novel signaling pathway by which sGC1 is affecting cells. The other gene, ETV1, encodes an Ets transcription factor. It was recently reported that TMPRSS2, an AR-regulated gene, was reported to fuse to the ETV1 gene in a subset of prostate cancers, suggesting an important role for ETV1 in prostate cancer. Our data strongly suggest that AR enhances the invasion capacity of prostate cancer cells by inducing the expression of ETV1, which can regulate the expression of, among several genes, MMP genes. These data, together with increased expression of ETV1 in prostate tumors, led us to hypothesize that ETV1 is an AR-regulated gene that mediates the pro-invasive effect of AR in prostate cancer. sGC1 and ETV1 provide two novel androgen-regulated genes that may be mediating the proliferative and invasive, respectively, activities of AR in prostate cancer.

 

Publications

Cai C, Hsieh CL, Omwancha J, Zheng Z, Chen SY, Baert JL, Shemshedini L. (2007) ETV1 Is a Novel Androgen Receptor-Regulated Gene That Mediates Prostate Cancer Cell Invasion. Mol. Endocrinol. [Epub ahead of print]

 

Cai C, Hsieh C, Shemshedini L. (2007) c-Jun Has Multiple Enhancing Activities in the Novel Cross Talk between the Androgen Receptor and Ets Variant Gene 1 in Prostate Cancer. Mol. Cancer Res.  [In press]

 

Cai C, Omwancha J, Hsieh CL, Shemshedini L. (2007) Androgen induces expression of the multidrug resistance protein gene MRP4 in prostate cancer cells. Prostate Cancer Prostatic Dis.10(1):39-45.

 

Cai C, Chen SY, Zheng Z, Omwancha J, Lin MF, Balk SP, Shemshedini L. (2007) Androgen regulation of soluble guanylyl cyclasealpha1 mediates prostate cancer cell proliferation. Oncogene. 26(11):1606-1615.

 

Cai C, Chen SY, Zheng Z, Omwancha J, Lin MF, Balk SP, Shemshedini L. (2007) Androgen regulation of soluble guanylyl cyclasealpha1 mediates prostate cancer cell proliferation. Oncogene 26(11):1606-15.

Omwancha, J., Zhou, X-F., Chen, S.Y., Baslan, T., Fisher, C.F., Zheng, Z., Cai, C., Shemshedini, L. (2006) Makorin RING finger protein 1 (MKRN1) has negative and positive effects on RNA polymerase II-dependent transcription. Endocrine 29, 363-373.

Zheng, Z., Cai, C., Omwancha, J., Chen, S.Y., Baslan, T., Shemshedini, L. (2006) SUMO-3 enhances androgen receptor transcriptional activity through a sumoylation-independent mechanism in prostate cancer cells. J. Biol. Chem. 281, 4002-4012.

Salas, T.R., Kim, J., Vakar-Lopez, F., Sabichi, A.L., Troncoso, P., Jenster, G., Kikuchi, A., Chen, S.Y.,Shemshedini, L., Suraokar, M., Logothetis, C.J., DiGiovanni, J., Lippman, S.M., Menter, D.G. (2004) Glycogen synthase kinase-3 beta is involved in the phosphorylation and suppression of androgen receptor activity. J. Biol. Chem. 279, 19191-19200.

Bubulya, A., Chen, S-Y., Fisher, C.J., Zheng, Z., Shen, X-Q., and Shemshedini, L. (2001) c-Jun potentiates the functional interaction between the amino and carboxy termini of the androgen receptor. J. Biol. Chem. 276, 44704-44711.

Shenk, J.L., Fisher, C.J., Chen, S-Y., Zhou, X-F., Tillman, K., and Shemshedini, L. (2001) p53 represses androgen-induced transactivation of prostate-specific antigen by disrupting hAR amino-to-carboxy terminal interaction. J. Biol. Chem. 276, 38742-38749.