Roles of Cyclin D3 in Neoplastic Proliferation

Cyclin D3 在肿瘤增殖中的作用

基本信息

批准号：
7354843
负责人：
MARCELO Luis RODRIGUEZ-PUEBLA
金额：
$ 22.65万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-02-28
项目状态：
已结题

项目摘要

A large number of human and experimental cancers display genetic alterations that activate G1-control kinases (CDK4 and CDK6). In this process, aberrant levels"ofD-type cyclins provide a growth advantage over normal cells. Whereas a role for cyclin D1 and D2 in cell proliferation have been established, recent data suggests that cyclin D3 (eye D3) plays additional roles in differentiation and growth arrest. This data correlates well with our preliminary results suggesting a role of eye D3 as a negative regulator of keratinocyte proliferation. Notably, overexpression of this cyclin results in inhibition of tumor development and decreased malignant progression to squamous cell carcinomas (SCC). Analysis of primary keratinocytes shows that overexpression of eye D3 results in strong reduction of the eye D2 protein levels, whereas elevated levels of eye D2 was observed in eye D3 null mice. Thus, we have hypothesized that eye D3 negatively regulate keratinocyte proliferation through a posttranslational mechanism downregulating eye D2. Supporting this hypothesis, cell lines derived from keratinocytes, papillomas and SCC, showed increased eye D3 stability in all but the SCC cell lines, whereas cell lines derived from SCC showed elevated stability of eye D1 suggesting that these two cyclins play opposing roles. To determine the potential application of D-type cyclins as target for therapeutic intervention it is essential to understand the role of each member. The work performed for this application has led to a number of relevant questions related to the roles of D-type cyclins in neoplastic development and epidermal homeostasis. However, in order to remain focused, we will concentrate on the role of eye D3 and eye D2 in tumorigenesis. Based on the preliminary results obtained for this application, we proposed two hypotheses: 1- Cyc D3 expression inhibits tumorigenesis through a posttranslational mechanism that results in decreased levels of eye D2 changing the proliferative capacity of epidermal cells. 2- Cyc D3 expression inhibits carcinogenesis by positive regulation of the differentiation process. In order to investigate these hypotheses, we propose the following specific aims: SA 1: To determine the effect of unbalanced expression of D-type cyclins in tumorigenesis. SA 2: To determine the posttranslational mechanism that regulates the levels of cyclin D2. SA 3: To determine the role of cyclin D3/CDK6 complexes in normal and neoplastic proliferation, and keratinocyte differentiation.

大量人类和实验癌症表现出激活 G1 控制的基因改变激酶（CDK4 和 CDK6）。在此过程中，D型细胞周期蛋白的异常水平提供了生长优势超过正常细胞。尽管细胞周期蛋白 D1 和 D2 在细胞增殖中的作用已经确定，但最近数据表明，细胞周期蛋白 D3（eye D3）在分化和生长停滞中发挥着额外的作用。这个数据与我们的初步结果很好地相关，表明眼睛 D3 作为角质形成细胞的负调节剂的作用增殖。值得注意的是，这种细胞周期蛋白的过度表达会抑制肿瘤的发展并减少恶性进展为鳞状细胞癌（SCC）。原代角质形成细胞的分析表明眼睛 D3 的过度表达会导致眼睛 D2 蛋白水平大幅降低，而眼睛 D2 蛋白水平升高在眼 D3 缺失小鼠中观察到眼 D2。因此，我们假设眼睛 D3 负调节通过下调 Eye D2 的翻译后机制促进角质形成细胞增殖。支持这个假设，源自角质形成细胞、乳头状瘤和鳞状细胞癌的细胞系，在除 SCC 细胞系外的所有细胞系，而源自 SCC 的细胞系显示眼睛 D1 的稳定性提高表明这两种细胞周期蛋白发挥相反的作用。确定D型的潜在应用细胞周期蛋白作为治疗干预的靶标，了解每个成员的作用至关重要。工作为此应用进行的研究引发了许多与 D 型细胞周期蛋白的作用相关的问题肿瘤发展和表皮稳态。然而，为了保持专注，我们将重点关注eye D3和eye D2在肿瘤发生中的作用。根据获得的初步结果在此应用中，我们提出了两个假设： 1- Cyc D3 表达通过以下途径抑制肿瘤发生：翻译后机制导致眼睛 D2 水平降低，改变增殖能力表皮细胞。 2- Cyc D3 表达通过分化的正调节抑制癌发生过程。为了研究这些假设，我们提出以下具体目标： SA 1：确定 D 型细胞周期蛋白不平衡表达在肿瘤发生中的影响。 SA 2：确定调节细胞周期蛋白 D2 水平的翻译后机制。 SA 3：确定细胞周期蛋白的作用 D3/CDK6 复合物参与正常和肿瘤性增殖以及角质形成细胞分化。