Tumor Suppression by Protein Kinase C-delta

描述（由申请方提供）：蛋白激酶C δ（PKC d）负调节细胞 已被认为是肿瘤抑制基因。符合本 假设，PKC d基因定位于染色体3 p上的一个区域，其中几个肿瘤抑制基因被认为存在。虽然已经确定了PKC d作为增殖负调节因子的作用，但对于PKC d如何发挥这种作用以及PKC d功能在人类癌症中是否受到抑制或丧失知之甚少。该提案的主要目标是确定PKC d如何影响人类乳腺癌细胞的细胞增殖和存活。对乳腺癌细胞系的初步研究表明，在具有不同癌表型的不同乳腺癌细胞系中，PKC d表达水平存在非随机差异。我们建议，肿瘤抑制作用的PKC d可以利用负调控细胞增殖和诱导凋亡的人乳腺癌细胞。具体而言，我们建议： 目的1：研究不同基因缺陷乳腺癌细胞株中蛋白激酶C d的表达。我们将确定PKC d的表达是否与特定的遗传改变如p53状态、雌激素受体丢失或酪氨酸激酶表达相关。 目的2：探讨蛋白激酶C d活性对乳腺癌细胞周期进程和凋亡的影响。 目的3：研究PKC d的表达是否能增强p53的表达，以及PKC d激动剂如苔藓抑素1（bryostatin 1）和bistrateneA是否能增强p53的表达。 目的4：研究蛋白激酶C d在抑制肿瘤转移中的作用。我们将 检测PKC d对细胞迁移、侵袭和蛋白酶分泌的影响。 这里提出的研究将表征肿瘤状态的一个潜在的重要指标--即具有不同遗传背景的乳腺癌细胞中PKC d的表达。基于已经揭示p53表达需要PKC d的初步研究，提出抑制PKC d将通过阻止p53的表达而具有促肿瘤作用。更重要的是，用苔藓抑素1等化合物激活PKC d可能具有肿瘤抑制作用，可以用于治疗。

DESCRIPTION (provided by applicant): Protein kinase C delta (PKC d) negatively regulates cell cycle progression and has been proposed to be a tumor suppresser gene. Consistent with this hypothesis, the PKC d gene localizes to a region on chromosome 3p where several tumor suppresser genes are thought to reside. While a role for PKC d as a negative regulator of proliferation has been established, little is known as to how PKC d exerts this effect, nor whether PKC d function is suppressed or lost in human cancer. The major objective for this proposal is to determine how PKC d impacts upon cell proliferation and survival in human breast cancer cells. Preliminary studies with breast cancer cell lines indicate non-random differences in the level of PKC d expression in different breast cancer cell lines with different cancerous phenotypes. We propose that tumor-suppressing effects of PKC d can be exploited to negatively regulate cell proliferation and induce apoptosis in human breast cancer cells. Specifically, we propose to: Aim 1: To characterize PKC d expression in breast cancer cell lines with different genetic defects. We will determine whether expression of PKC d correlates with specific genetic alterations such as p53 status, loss of estrogen receptor, or tyrosine kinase expression. Aim 2: To characterize the impact of PKC d activity upon cell cycle progression and apoptosis in breast cancer cells. Aim 3: To determine whether p53 expression can be enhanced by elevated expression of PKC d or by PKC d agonists such as bryostatin1 and bistratene A. Aim 4: To characterize the role that PKC d plays in suppressing metastatic phenotypes. We will examine the effect of PKC d upon cell migration, invasion and protease secretion. The studies proposed here will characterize a potentially important indicator of tumor status--that being the expression of PKC d in breast cancer cells with different genetic backgrounds. Based on preliminary studies that have revealed a PKC d requirement for p53 expression, it is proposed that inhibiting PKC d would have tumor-promoting effects by preventing the expression of p53. And more importantly, activating PKC d with compounds like bryostatin1 could have tumor suppressing effects that could be exploited therapeutically.