Roles of Cyclin D3 in Neoplastic Proliferation

Cyclin D3 在肿瘤增殖中的作用

• 批准号: 7767010
• 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 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7767010
• 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表现出激活G1控制的基因改变。 激酶(CDK4和CDK6)。在这个过程中，d型细胞周期蛋白的异常水平提供了生长优势。 而不是正常细胞。鉴于细胞周期蛋白D1和D2在细胞增殖中的作用已被证实，最近 数据表明，细胞周期蛋白D3(眼睛D3)在分化和生长停滞中起着额外的作用。此数据 与我们的初步结果很好地关联，表明眼睛D3作为角质形成细胞的负调节因子的作用 扩散。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 恶性进展为鳞状细胞癌(SCC)。对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蛋白水平的显著降低，而 在眼D3基因缺失的小鼠中观察到眼D2。因此，我们假设眼睛D3负向调节 角质形成细胞通过翻译后机制下调眼睛D2的增殖。支持这一点 假说，来源于角质形成细胞、乳头状瘤和鳞癌的细胞系显示，眼部D3稳定性在 除鳞状细胞癌细胞系外，其他所有细胞系均显示出Eye D1的稳定性升高 这表明这两个周期扮演着相反的角色。确定D型的潜在应用 作为治疗干预的靶点，了解每个成员的作用是至关重要的。这项工作 导致了一些与D型细胞周期蛋白的作用相关的问题 在肿瘤发育和表皮动态平衡方面。然而，为了保持专注，我们将 集中在眼睛D3和眼睛D2在肿瘤发生中的作用。根据从以下方面获得的初步结果 在这一应用中，我们提出了两个假设：1-Cyc D3的表达通过一种 导致眼球D2水平降低改变细胞增殖能力的翻译后机制 表皮细胞。2-Cyc D3的表达通过正向调节分化抑制肿瘤的发生 进程。为了研究这些假设，我们提出了以下具体目标：SA 1： 确定D-型细胞周期蛋白表达失衡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。答案3：确定细胞周期蛋白的作用 D3/CDK6复合体在正常和肿瘤中的增殖，以及角质形成细胞的分化。