Androgen receptor (AR) plays an important role in the development and growth, as well as pathogenesis of prostate. Our recent results indicate that AR activity can be modulated by SRY, the male sex-determining factor. The AR/SRY directly interact with each other via their respective DNA binding domains. The SRY DNA binding domain, the HMG, is highly conserved among its family members, namely the SOX proteins. In deed, the AR DBD can interact with a variety of SOX proteins. AR was also able to suppress SRY/SOX9 transciptional activation. Moreover, SRY can interact with other steroid hormone receptors, such as estrogen and glucocoticoid receptors, but not with the related nuclear receptor, thyroid receptor. These results suggest that there is a general and specific protein interaction between the SRY/SOX and steroid hormone receptor family proteins. SRY protein has been detected in the prostate tissue, cDNA microarray analysis has reveals the presence of several SOX proteins in the normal prostate and prostate cancers. This proposal is define the biological significance of the interaction of AR and SRY/SOX families, which are both proven to be crucial for cell and tissue growth and differentiation. Studies are designed to address the mechanism of AR and SRY/SOX protein interaction.
Aim 1. is to will determine the molecular details of AR-SRY interaction domains by mutational analysis.
Aim 2. is to define the potential mechanism of AR-SRY mutual inhibition and test the hypothesis whether the inhibition mediated through interference of DNA binding; through recruitment of corepressor(s); or by interference of coactivator binding to AR or of AR N- and C-terminal interaction.
Aim 3 it to assess the temporal and cell specific SRY/SOX protein expression in normal and abnormal prostate, which will shed light to their potential role in modulating AR functions. These studies will provide new understandings to the biological mechanisms of normal prostate development, to the pathogenesis of prostate hyperplasia and cancer. SRY mediated AR interference may also provide a tool for the design of more efficiently and specifically AR antagonist. My carrier goal is to become an independent physician scientist and doing research, which will lead to better understanding of human health and disease. This grant will allow me protected time to further expand my knowledge on uroglocal pathology, sharpen grant writing skills and general new data that will lead to future success in RO1 application.
|Wang, Hongyun; Leav, Irwin; Ibaragi, Soichiro et al. (2008) SOX9 is expressed in human fetal prostate epithelium and enhances prostate cancer invasion. Cancer Res 68:1625-30|
|Wang, Hongyun; McKnight, Nicole C; Zhang, Tao et al. (2007) SOX9 is expressed in normal prostate basal cells and regulates androgen receptor expression in prostate cancer cells. Cancer Res 67:528-36|
|Yuan, Xin; Li, Tong; Wang, Hongyun et al. (2006) Androgen receptor remains critical for cell-cycle progression in androgen-independent CWR22 prostate cancer cells. Am J Pathol 169:682-96|