Roles of Cyclin D3 in Neoplastic Proliferation

Cyclin D3 在肿瘤增殖中的作用

• 批准号: 7580956
• 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
• 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/7580956
• 关键词: Ablation; Biochemical; CDK4 gene; Cell Line; Cell Proliferation; Cells; Complex; Cyclin D1; Cyclins; Data; Development; Differentiation and Growth; Epidermis; Equilibrium; Eye; F-Box Proteins; Family; Growth; Hand; Homeostasis; Human; Knockout Mice; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Messenger RNA; Mus; Mutation; Normal Cell; Nuclear; Papilloma; Phosphotransferases; Play; Process; Proteins; Regulation; Research Personnel; Role; Squamous cell carcinoma; Therapeutic Intervention; Tissues; Ubiquitination; Work; base; carcinogenesis; cyclin D2; cyclin D3; in vitro Assay; keratinocyte; keratinocyte differentiation; member; neoplastic; overexpression; programs; tumor; tumorigenesis

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.

大量的人类和实验性癌症显示出激活G1控制的遗传改变 激酶（CDK4和CDK6）。在此过程中，异常水平“ Ofd型细胞周期蛋白都提供了增长优势 在正常细胞上。虽然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 数据表明Cyclin D3（Eye D3）在分化和生长停滞中起着其他作用。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表达导致抑制肿瘤的发展并减少 恶性向鳞状细胞癌（SCC）进展。对主要角质形成细胞的分析表明 眼睛D3的过表达导致眼睛D2蛋白水平的大大降低，而升高的水平 眼睛D2在Eye D3 Null小鼠中观察到。因此，我们假设眼睛D3负调节 通过下调眼D2的翻译后机制的角质形成细胞增殖。支持这个 假设，源自角质形成细胞，乳头状瘤和SCC的细胞系显示了眼睛D3稳定性的增加 除SCC细胞系以外的所有内容，而从SCC得出的细胞系显示了眼睛D1的稳定性升高 表明这两个细胞周期蛋白扮演着相反的角色。确定D型的潜在应用 细胞周期蛋白作为治疗干预的靶标，必须了解每个成员的作用。工作 为此应用程序执行的导致许多相关问题与D型细胞周期蛋白的角色有关 在肿瘤发育和表皮稳态中。但是，为了保持专注，我们将 专注于眼睛D3和眼睛D2在肿瘤发生中的作用。根据获得的初步结果 该应用，我们提出了两个假设：1- CYC D3表达通过A抑制肿瘤发生 翻译后机制导致眼睛D2的水平降低，改变了增生能力 表皮细胞。 2- CYC D3表达通过分化的阳性调节抑制了癌变 过程。为了调查这些假设，我们提出以下具体目的：SA 1： 确定D型细胞周期蛋白在肿瘤发生中的不平衡表达的影响。 SA 2：确定 调节细胞周期蛋白D2水平的翻译后机制。 SA 3：确定细胞周期蛋白的作用 正常和肿瘤增殖和角质形成细胞分化的D3/CDK6复合物。