Roles of Cyclin D3 in Neoplastic Proliferation

Cyclin D3 在肿瘤增殖中的作用

• 批准号: 7091228
• 负责人: MARCELO Luis RODRIGUEZ-PUEBLA
• 金额: $ 22.92万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/7091228
• 关键词: carcinogenesis; cell differentiation; cell growth regulation; cell line; cell proliferation; cyclin dependent kinase; cyclins; enzyme complex; genetic regulation; genetically modified animals; keratinocyte; laboratory mouse; molecular oncology; neoplasm /cancer genetics; posttranslational modifications; protein structure function; squamous cell carcinoma

DESCRIPTION (provided by applicant): A large number of human and experimental cancers display genetic alterations that activate G1-control kinases (CDK4 and CDK6). In this process, aberrant levels "of D-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 (cyc D3) plays additional roles in differentiation and growth arrest. This data correlates well with our preliminary results suggesting a role of cyc 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 cyc D3 results in strong reduction of the cyc D2 protein levels, whereas elevated levels of cyc D2 was observed in cyc D3 null mice. Thus, we have hypothesized that cyc D3 negatively regulate keratinocyte proliferation through a posttranslational mechanism downregulating cyc D2. Supporting this hypothesis, cell lines derived from keratinocytes, papillomas and SCC, showed increased cyc D3 stability in all but the SCC cell lines, whereas cell lines derived from SCC showed elevated stability of cyc 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 cyc D3 and cyc 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 cyc 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.

描述（由申请人提供）：大量人类和实验癌症表现出激活 G1 控制激酶（CDK4 和 CDK6）的基因改变。在此过程中，D 型细胞周期蛋白的异常水平提供了优于正常细胞的生长优势。虽然细胞周期蛋白 D1 和 D2 在细胞增殖中的作用已经确定，但最近的数据表明细胞周期蛋白 D3 (cyc D3) 在分化中发挥着额外的作用该数据与我们的初步结果很好地相关，表明 cyc D3 作为角质形成细胞增殖的负调节剂。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降低恶性程度。原发性角质形成细胞的分析表明，cyc D3 的过度表达导致 cyc D2 蛋白水平大幅降低，而在 cyc D3 缺失小鼠中观察到 cyc D2 水平升高。 cyc D3 通过下调 cyc D2 的翻译后机制负向调节角质形成细胞增殖，来自角质形成细胞、乳头状瘤的细胞系支持这一假设。和 SCC 中，除 SCC 细胞系外，所有细胞系均显示 cyc D3 稳定性增加，而源自 SCC 的细胞系显示 cyc D1 稳定性增加，表明这两种细胞周期蛋白发挥相反的作用。为了确定 D 型细胞周期蛋白作为治疗干预靶标的潜在应用，必须了解每个成员的作用。为此应用所做的工作引发了许多与 D 型细胞周期蛋白在肿瘤发展和表皮稳态中的作用相关的问题。然而，为了保持重点，我们将重点关注 cyc D3 和 cyc D2 在肿瘤发生中的作用。基于该应用获得的初步结果，我们提出了两个假设： 1- Cyc D3 表达通过翻译后机制抑制肿瘤发生，导致 cyc D2 水平降低，从而改变表皮细胞的增殖能力。 2- Cyc D3 表达通过正向调节分化过程来抑制癌发生。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 D3/CDK6 复合物在正常和肿瘤增殖以及角质形成细胞分化中的作用。