Role of cyclin-dependent Kinase 5 in cell proliferation

细胞周期蛋白依赖性激酶 5 在细胞增殖中的作用

• 批准号: 312985-2011
• 负责人: Lee, KiYoung
• 金额: $ 3.5万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=526628
• 关键词: Role; cyclin; dependent; Kinase; cell

My research program is geared towards understanding how protein kinases regulate cell function. The focus is to unravel the molecular mechanisms by which cyclin dependent kinase 5 (cdk5) regulates specific cellular processes. Indeed, the phosphorylation mechanisms involving cdk5 are intriguing as mice lacking cdk5 exhibit embryonic lethality, indicating that cdk5 is essential for development and survival. My general hypothesis is that cdk5 is key to an elaborate system of protein-protein interactions and phosphorylation events in the mammalian cell. To address this premise, my broad research program encompasses questions that include: how cdk5 activity is regulated, what the molecular targets of cdk5 are and how cdk5 interacts with its targets, and how cdk5 participates in signaling pathways to regulate cell fate, including proliferation, differentiation, and apoptosis. Currently, our investigations are primarily directed at examining cdk5 regulation and role in spermiogenesis, cilia formation and function, and cell proliferation. Indeed, while cdk5 activity has mostly been associated with postmitotic neurons, there is now substantial evidence of apoptosis-independent cdk5 activity in proliferating cells. Interestingly, there are also new reports implicating a role for cdk5 in the cell cycle. Consistent with these findings, we recently observed that cdk5-/- embryos are bigger and have increased genomic DNA (gDNA) levels compared to their wt littermates. In addition, we found that cdk5-/- mouse embryonic fibroblasts (MEFs) proliferate at a faster rate than wt MEFs, supporting the idea of a novel function of cdk5 in cell proliferation. Therefore, my focus in this application is to explore my specific hypothesis that cdk5 serves to inhibit cell cycle progression. My specific objective is to utilize the cdk5 knockout system to: (i) investigate whether the increase in size of cdk5-/- mouse embryos is due to increased number of cells, (ii) determine the specific phase(s) of the cell cycle that is inhibited by cdk5, and (iii) investigate the molecular mechanism(s) by which cdk5 may inhibit the cell cycle. Understanding how cdk5 controls the cell cycle will further advance our knowledge of this fundamental cellular process.

我的研究计划旨在了解蛋白激酶是如何调节细胞功能的。重点在于揭示细胞周期蛋白依赖性激酶5(CDK5)调控特定细胞过程的分子机制。事实上，涉及CDK5的磷酸化机制很有趣，因为缺乏CDK5的小鼠表现出胚胎致死性，表明CDK5对发育和生存是必不可少的。我的一般假设是，CDK5是哺乳动物细胞中蛋白质-蛋白质相互作用和磷酸化事件的复杂系统的关键。为了解决这一前提，我的广泛研究计划包括以下问题：CDK5活性是如何调节的，CDK5的分子靶点是什么，CDK5如何与其靶点相互作用，以及CDK5如何参与信号通路来调节细胞命运，包括增殖、分化和凋亡。目前，我们的研究主要针对CDK5在精子发生、纤毛形成和功能以及细胞增殖中的调控和作用。事实上，虽然CDK5的活性主要与有丝分裂后的神经元有关，但现在有大量证据表明，在增殖的细胞中，CDK5的活性不依赖于凋亡。有趣的是，也有新的报告暗示了CDK5在细胞周期中的作用。与这些发现一致，我们最近观察到CDK5-/-胚胎比它们的wt胎更大，并且有更高的基因组DNA(GDNA)水平。此外，我们发现CDK5-/-小鼠胚胎成纤维细胞(MEF)的增殖速度比wt MEF更快，支持了CDK5在细胞增殖中的新功能的想法。因此，我在这项应用中的重点是探索我的特定假设，即CDK5服务于抑制细胞周期进程。我的具体目标是利用CDK5基因敲除系统：(I)研究CDK5-/-小鼠胚胎尺寸的增加是否是由于细胞数量的增加，(Ii)确定CDK5抑制细胞周期的特定时相(S)，以及(Iii)研究CDK5抑制细胞周期的分子机制(S)。了解CDK5是如何控制细胞周期的，将进一步促进我们对这一基本细胞过程的了解。