THE ROLE OF ANNEXIN I DOWN-REGULATION IN PROSTATE CANCER

描述(由申请人提供)：膜联蛋白I蛋白表达下调是前列腺癌发生中的一个重要事件。我们的假设是，膜联蛋白I通过稳定早期内体隔膜中的蛋白激酶C(PKC)和促进细胞凋亡来控制细胞增殖和细胞死亡之间的平衡。我们认为，质膜相关的PKCalpha通过激活ERK优先诱导增殖，而定位于早期内膜室的PKCalpha通过激活p38和Akt的去磷酸化优先诱导细胞凋亡。我们提出了一个模型来解释前列腺癌的发生，在这个模型中，Annexin I下调导致内体隔膜中激活的PKCalpha不稳定，阻止再循环到质膜。质膜上活化的PKCalpha减少的结果是Akt的激活增强和延长，p38的激活减少，从而导致非拮抗的ERK介导的增殖。本研究的目的是确定：1)减少良性前列腺上皮细胞膜联蛋白I的表达对细胞增殖、凋亡以及Akt、p38和ERK激活的影响；2)膜联蛋白I是否调节RAS活性；3)膜联蛋白I在调节细胞定位和PKCalpha活性中的作用。具体目标：1)确定下调良性前列腺上皮细胞膜联蛋白I表达的生物学影响；2)确定膜联蛋白I是否调节RAS活性；3)确定膜联蛋白I表达是否以及如何影响PKCalpha的细胞定位和活性。

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.