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）：大量人类和实验性癌症显示出激活G1-控制激酶（CDK 4和CDK 6）的遗传改变。在这个过程中，D型细胞周期蛋白的异常水平提供了比正常细胞更大的生长优势。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）在分化和生长停滞中起着额外的作用。该数据与我们的初步结果相关，表明cyc D3作为角质形成细胞增殖的负调节剂的作用。值得注意的是，这种细胞周期蛋白的过表达导致肿瘤发展的抑制和鳞状细胞癌（SCC）恶性进展的减少。对原代角质形成细胞的分析表明，cyc D3的过表达导致cyc D2蛋白水平的强烈降低，而在cyc D3缺失小鼠中观察到cyc D2水平升高。因此，我们假设cyc D3通过下调cyc D2的翻译后机制负调控角质形成细胞增殖。支持这一假设，细胞系来源于角质形成细胞，乳头状瘤和SCC，显示增加的细胞周期蛋白D3的稳定性，但SCC细胞系，而细胞系来源于SCC显示升高的稳定性的细胞周期蛋白D1表明，这两个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点的潜在应用，了解每个成员的作用是至关重要的。这项工作的应用导致了一些相关的问题，D型细胞周期蛋白在肿瘤的发展和表皮稳态的作用。然而，为了保持重点，我们将集中在细胞色素D3和细胞色素D2在肿瘤发生中的作用。基于本申请获得的初步结果，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，该机制导致Cyc D2水平降低，从而改变表皮细胞的增殖能力。2-Cyc D3的表达通过对分化过程的正性调节来抑制癌发生。为了研究这些假设，我们提出了以下具体目标：SA 1：确定D型细胞周期蛋白的不平衡表达在肿瘤发生中的作用。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/CDK 6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。