THE ROLE OF ANNEXIN I DOWN-REGULATION IN PROSTATE CANCER

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DESCRIPTION (provided by applicant): Down-regulation of annexin I protein expression is an important event in prostate cancer initiation. Our hypothesis is that annexin I controls the balance between proliferation and cell death by stabilizing protein kinase C (PKC) in the early endosomal compartment and facilitating apoptosis. We propose that plasma membrane associated PKCalpha preferentially induces proliferation by activating ERK while PKCalpha localized to the early endosomal compartment preferentially induces apoptosis through activation of p38 and dephosphorylation of Akt. We propose a model to explain prostate carcinogenesis whereby annexin I downregulation leads to destabilization of activated PKCalpha in the endosomal compartment preventing recycling to the plasma membrane. The consequence of decreased activated PKCalpha in the plasma membrane is enhanced and prolonged Akt activation and reduced p38 activation leading to unopposed ERK mediated proliferation. The objectives of the proposed study are to determine; 1) the impact of reducing annexin I expression in benign prostatic epithelial cells on cellular proliferation, apoptosis, as well as Akt, p38 and ERK activation, 2) if annexin I modulates Ras activity and 3) the role annexin I plays in regulating cellular localization and activity of PKCalpha. SPECIFIC AIMS: 1) Determine the biologic impact of down-regulating annexin I expression in benign prostatic epithelial cells 2) Determine if annexin I regulates Ras activity 3) Determine if and how annexin I expression effects cellular location and activity of PKCalpha.