Recent data suggest that excessive c-Myc expression is important in maintaining and preventing the regression of prostate cancer. Separate studies have shown that MBP1 can cause prostate cancer regression in mouse systems. A rapid convergence of evidence from our laboratory and others led us to hypothesize that MBP1 and Myc are interacting in prostate cancer cells to affect tumor progression. Yeast-two-hybrid screening for proteins that interact with Myc yielded several independent isolates of MBP1. Interestingly, Myc and MBP1 have striking functional similarities with regard to apoptosis and gene repression, processes that have direct implications for cancer progression. Considering the role of Myc and the specific role of MBP1 in prostate cancer, we therefore hypothesize that the interaction between MBP1 and Myc is a key determinant of malignancy in prostate cancer. We aim (1) to confirm the interaction between Myc and MBP1 and determine if this interaction is prostate cancer specific; (2) to determine if MBP1 affects Myc's regulation of target genes; and (3) to determine if the MBP1-Myc interaction affects cellular transformation and cancer-affecting processes. Our preliminary data suggest that there is a strong interaction between Myc and MBP1. We have characterized antibodies and siRNA sequences that can be effectively used to detect and knock down MBP1. Using these tools and others, we will confirm the Myc-MBP1 interaction using coimmunoprecipitation (coIP) experiments. We will also use coIP to identify mutants of each protein that cannot bind the other. We will use quantitative PCR and chromatin IP to establish if MBP1 affects Myc gene regulation, particularly gene repression. We will use the TUNEL assay to determine if MBP1 and Myc affect each other's apoptosis-inducing properties. Finally, we will assay the effect that the Myc-MBP1 interaction has on cellular transformation, examining anchorage-independent growth, loss of contact inhibition, and the ability to produce a tumor in nude mice. These experiments will be complemented with parallel studies in nonprostate and noncancer cells to determine if the interaction, or its properties, are prostate or, more importantly, prostate cancer specific. These data can potentially yield a diagnostic assay for early detection of prostate cancer. They can also expose an Achilles' heel of prostate cancer against which drugs can be targeted.
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