EXCEED THE SPACE PROVIDED. Since the first identification of the role of CypA in CsA-induced immunosuppression, its cellular function becomes only slowly unraveled. Recently, different aspects of biological functions of CypA have emerged that provide an invaluable means for further understanding the function of CypA in cellular regulation. Since our first identification of CypA as an Rb associated protein, we have attempted further characterization of cellular function of CypA. Our recent data show that shRNA for targeting CypA have resulted in several altered phenotypes in P19 EC cells and osteosarcoma cell line, U2OS. The altered phenotypes: 1) have increased cell growth rates and have lost their potential for retinoic acid (RA)-induced neuronal differentiation; 2) have lost their response to both retinoic acid (RA) and bone morphogenetic protein (BMP)- 4 (RA/BMP4)-induced apoptosis; 3) have a disorganizing F-actin and reduced cell migratory activity and transformation capacity in CypA knocked-down U2OS cells. These data suggest that CypA is involved in multiple pathways in cellular regulation. These data have led us hypothesize that CypA acts as a chaperon to change the expression of a set of genes that play pivotal roles in determining cell fate, signaling and morphology. To test this hypothesis, we propose the following specific aims: 1. Elucidate the mechanism by which CypA is involved in the effect of RA/BMP-4-induced programmed cell death of P19 EC cells; 2. Elucidate the mechanism by which CypA affects the processing of RA-induced neuronal differentiation of P19 EC Cells; 3. Study the role of CypA for F-actin assembly in U2OS, and the possibility of applying the down-regulated CypA to cancer therapy. If CypA is proven to be an important in modulating the expression of a set of genes such as msxl and gasl, it can aid us further understanding the CypA network in regulation of cellular functions. In addition, a close link between the inactivation of CypA and induction of DNA hypermethylation of Peg3 can also impact our knowledge in tumorigenesis. Lastly, CypA can be tremendously useful as a therapeutic target, since down-regulated CypA alters actin cytoskeleton, which leads to reduce tumor cells growth, transformation capacity, alteration of signaling, and sensitizing cells to chemotherapeutic agents. * The role of CypA is involved in multiple pathways in cellular regulations. It can be useful as a therapeutic target as it can switch on-off a regulatory protein leading cancer cells to death. PERFORMANCE SITE ========================================Section End===========================================
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