THE ROLE OF ANNEXIN I DOWN-REGULATION IN PROSTATE CANCER

附件蛋白 I 下调在前列腺癌中的作用

• 批准号: 6919336
• 负责人: DAVID K ORNSTEIN
• 金额: $ 15.25万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919336
• 关键词: RNA interference; annexins; apoptosis; biological signal transduction; carcinogenesis; cell proliferation; green fluorescent proteins; guanine nucleotide binding protein; mitogen activated protein kinase; prostate neoplasms; protein kinase C; protein localization

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.

描述（申请人提供）：膜联蛋白I表达下调是前列腺癌起始的重要事件。我们的假设是膜联蛋白I通过稳定早期内体室中的蛋白激酶C （PKC）和促进细胞凋亡来控制增殖和细胞死亡之间的平衡。我们提出质膜相关PKCalpha通过激活ERK优先诱导增殖，而定位于早期内体室的PKCalpha通过激活p38和Akt去磷酸化优先诱导凋亡。我们提出了一个模型来解释前列腺癌的发生，其中膜联蛋白I下调导致内体腔室中活化PKCalpha的不稳定，从而阻止了质膜的再循环。质膜中PKCalpha活化减少的结果是Akt活化延长，p38活化减少，导致无对抗ERK介导的增殖。拟议研究的目的是确定；1)降低良性前列腺上皮细胞中膜联蛋白I的表达对细胞增殖、凋亡以及Akt、p38和ERK活化的影响；2)膜联蛋白I是否调节Ras活性；3)膜联蛋白I在调节PKCalpha的细胞定位和活性中的作用。特异性目的：1)确定下调膜联蛋白I表达在良性前列腺上皮细胞中的生物学影响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。