My long-term goal is to study the biology of stromal-epithelial interactions in benign prostatic hyperplasia (BPH). Since development, growth and tumorigenesis in the prostate is closely regulated by the stromal-epithelial crosstalk, identifying the signal transduction pathways between prostate epithelial cells and the surrounding stromal cells will enable us to better understand the normal and abnormal biology in prostatic diseases. I hypothesize that expression of particular stromal genes is one of the components that regulates the proliferation, cell death and differentiation of prostatic epithelial cells leading to BPH in adulthood. The Jun-family proteins that are early transcription factor molecules have been shown to regulate stromal-epithelial interactions via paracrine modulation. Moreover, the Jun family member proteins have been shown to play an important role in proper development of the genitourinary organs. The balance between the different Jun-family expression in the stroma may be one of the determinants of the ultimate survival or death signals that the stroma may exert on prostatic epithelial cells. This proposal will address whether paracrine signals form stromal cells with genetically modified Jun-family proteins can regulate epithelial proliferation, cell death and differentiation. Stromal expression of Jun-family proteins will be examined in relation to signal transduction pathways known to be important in prostatic stromal-epithelial interactions. These studies can improve our understanding of normal and abnormal stromal-epithelial interactions that may lead to BPH in adulthood.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK064062-03
Application #
6918563
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$131,328
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Zhang, Xiaoping; Huang, Xu; Olumi, Aria F (2009) Repression of NF-kappaB and activation of AP-1 enhance apoptosis in prostate cancer cells. Int J Cancer 124:1980-9
Zhang, Xiaoping; Li, Wenhua; Olumi, Aria F (2008) Overcoming resistance to trail-induced apoptosis in prostate cancer by regulation of c-FLIP. Methods Enzymol 446:333-49
Huang, Xu; Zhang, Xiaoping; Farahvash, Benyamin et al. (2007) Novel targeted pro-apoptotic agents for the treatment of prostate cancer. J Urol 178:1846-54
Zhang, Liang; Zhang, Xiaoping; Barrisford, Glen W et al. (2007) Lexatumumab (TRAIL-receptor 2 mAb) induces expression of DR5 and promotes apoptosis in primary and metastatic renal cell carcinoma in a mouse orthotopic model. Cancer Lett 251:146-57
Li, Wenhua; Zhang, Xiaoping; Olumi, Aria F (2007) MG-132 sensitizes TRAIL-resistant prostate cancer cells by activating c-Fos/c-Jun heterodimers and repressing c-FLIP(L). Cancer Res 67:2247-55
Li, Wenhua; Wu, Chin-Lee; Febbo, Phillip G et al. (2007) Stromally expressed c-Jun regulates proliferation of prostate epithelial cells. Am J Pathol 171:1189-98
Zhang, Xiaoping; Li, Wenhua; Olumi, Aria F (2007) Low-dose 12-O-tetradecanoylphorbol-13-acetate enhances tumor necrosis factor related apoptosis-inducing ligand induced apoptosis in prostate cancer cells. Clin Cancer Res 13:7181-90
Zhang, Xiaoping; Zhang, Liang; Yang, Hongmei et al. (2007) c-Fos as a proapoptotic agent in TRAIL-induced apoptosis in prostate cancer cells. Cancer Res 67:9425-34
San Francisco, Ignacio F; DeWolf, William C; Peehl, Donna M et al. (2004) Expression of transforming growth factor-beta 1 and growth in soft agar differentiate prostate carcinoma-associated fibroblasts from normal prostate fibroblasts. Int J Cancer 112:213-8