Coordinated cellular responses to diverse environmental inputs result from signal integration through crosstalk of signal transduction pathways. The behavior of prostate epithelial cells and progression of prostate carcinoma are regulated by androgens and TGF-beta, which activate two distinct signaling pathways that regulate normal and malignant cell functions and are of great physiological and pathological importance. Physical and functional interactions of the androgen receptor and TGF-beta-activated Smads have been implicated in the crosstalk of androgen and TGF-beta signaling. Here, I propose to determine the mechanisms of TGF-beta and androgen signaling crosstalk in regulating gene expression in prostate epithelial cells. Specifically, I will identify subsets of transcriptional targets that are differentially co-regulated by TGF-beta and androgens and define molecular mechanisms of signaling crosstalk at distinct promoters with differential transcriptional responses. This study will contribute to our understanding of mechanisms of signal integration in normal and malignant cell physiology and may provide a basis for mechanism-directed drug design for prostate cancer therapy. ? ? ?
