We have demonstrated that the homeodomain Nkx 3.1 is a potent activator of the smooth muscle gamma actin [SMGA] gene. Although Nkx 3.1 is expressed in a variety of embryonic tissues, it is an androgen regulated gene product whose expression in adults is largely restricted to the male urogenital tract, primarily prostatic epithelia. Recent experiments from our lab has demonstrated that SMGA mRNA is expressed in normal and cancerous prostate epithelial cells. Moreover, SMGA expression [protein and mRNA] has been demonstrated in prostatic epithelia and exhibit a change in expression in carcinogenic cells. Thus, we believe that SMGA represents a novel product of differentiated epithelia. To test this hypothesis, we will determine SMGA temporal and spatial expression during prostate development [AIM I]. These studies will utilize in situ, immunochemistry and transgenic techniques to determine if SMGA is activated in parallel with Nkx 3.1 in early prostate epithelial cell development or with its increased androgen-responsive expression obtained with puberty. We will also directly compare mouse and human prostate development and determine whether or not there is a link of SMGA expression or cellular localization with the progression of cancer. Further, we will determine the mechanism(s) that Nkx 3.1 and SRF utilize to activate prostatic SMGA expression and determine if interaction of these regulators is capable of reversing the aberrant growth control of prostatic tumor cells [AIM II]. Finally, we will utilize novel Cre/LoxP technologies to ablate the expression of SMGA and its regulator, Nkx 3.1, in developing and mature prostate epithelia [AIM III]. These experiments will determine the consequences of specifically eliminating these genes upon prostate morphological and functional capacity. When completed, these studies will provide a new understanding of the molecular mechanisms that underlie Prostate development. In addition, our studies will potentially develop new models of prostate cancer, thus providing not only an avenue for greater comprehension of prostate carcinogenesis, but also strategic knowledge for further studies to design molecular based therapies for advanced prostate cancer.
|Sun, Qiang; Taurin, Sebastien; Sethakorn, Nan et al. (2009) Myocardin-dependent activation of the CArG box-rich smooth muscle gamma-actin gene: preferential utilization of a single CArG element through functional association with the NKX3.1 homeodomain protein. J Biol Chem 284:32582-90|
|Verzi, Michael P; Stanfel, Monique N; Moses, Kelvin A et al. (2009) Role of the homeodomain transcription factor Bapx1 in mouse distal stomach development. Gastroenterology 136:1701-10|
|Young, Jennifer L; Zimmer, Warren E; Dean, David A (2008) Smooth muscle-specific gene delivery in the vasculature based on restriction of DNA nuclear import. Exp Biol Med (Maywood) 233:840-8|
|Zhang, Yan; Fillmore, Rebecca A; Zimmer, Warren E (2008) Structural and functional analysis of domains mediating interaction between the bagpipe homologue, Nkx3.1 and serum response factor. Exp Biol Med (Maywood) 233:297-309|
|Sampson, H Wayne; Dearman, Alaina C; Akintola, Adebayo D et al. (2007) Immunohistochemical localization of cadherin and catenin adhesion molecules in the murine growth plate. J Histochem Cytochem 55:845-52|
|Dean, D A; Strong, D D; Zimmer, W E (2005) Nuclear entry of nonviral vectors. Gene Ther 12:881-90|
|Stanfel, M N; Moses, K A; Schwartz, R J et al. (2005) Regulation of organ development by the NKX-homeodomain factors: an NKX code. Cell Mol Biol (Noisy-le-grand) Suppl 51:OL785-99|