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）：大量的人类和实验性癌症显示出激活G1控制激酶的遗传改变（CDK4和CDK6）。在此过程中，D型细胞周期蛋白的异常水平比正常细胞提供了生长的优势。尽管已经确定了细胞周期蛋白D1和D2在细胞增殖中的作用，但最近的数据表明，Cyclin D3（CYC D3）在差异和生长中扮​​演了额外的作用，这与我们的PRELIMINAL INDERINAL CALSIFERINES cyciratient a s a cyc d3相关。值得注意的是，这种细胞周期蛋白的过表达导致肿瘤发育的抑制作用，并降低了对鳞状细胞癌的进展（SCC）。通过下调CYC D2的翻译机制调节角质形成细胞的增殖，源自角质形成细胞的细胞系，乳头状瘤和SCC显示出除SCC细胞系以外的所有细胞系中的Cyc D3稳定性，而SCC均显示出cyc D1的稳定性升高。为了确定D型细胞周期蛋白的潜在应用作为治疗干预的靶标，必须了解每个成员的作用。针对此应用的工作导致了许多相关问题，与D型细胞周期蛋白在肿瘤发育和表皮稳态中的作用有关。但是，为了保持专注，我们将专注于CYC D3和CYC D2在肿瘤发生中的作用。基于该应用程序获得的初步结果，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，从而导致CYC D2降低的CYC D2降低，改变了表皮细胞的增殖能力。 2- CYC D3表达通过分化过程的阳性调节抑制癌变。为了研究这些假设，我们提出了以下特定目的：SA 1：确定D型细胞周期蛋白在肿瘤发生中不平衡表达的影响。 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中的作用，以及角质形成细胞分化。