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: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=548840
• 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.

我的研究项目是为了了解蛋白激酶如何调节细胞功能。 重点是阐明细胞周期蛋白依赖性激酶5（cdk 5）调节特定细胞过程的分子机制。 事实上，涉及cdk 5的磷酸化机制是有趣的，因为缺乏cdk 5的小鼠表现出胚胎致死性，表明cdk 5是发育和生存所必需的。 我的一般假设是cdk 5是哺乳动物细胞中蛋白质相互作用和磷酸化事件的复杂系统的关键。 为了解决这个前提，我的广泛的研究计划包括的问题，包括：cdk 5的活性是如何调节，cdk 5的分子靶点是什么，cdk 5如何与它的目标相互作用，以及cdk 5如何参与信号通路，以调节细胞的命运，包括增殖，分化和凋亡。 目前，我们的研究主要集中在研究cdk 5在精子发生、纤毛形成和功能以及细胞增殖中的调节和作用。 事实上，虽然cdk 5的活性主要与有丝分裂后的神经元，现在有大量的证据表明，在增殖细胞中的cdk 5活性与凋亡无关。 有趣的是，也有新的报道暗示cdk 5在细胞周期中的作用。 与这些发现相一致，我们最近观察到cdk 5-/-胚胎与其野生型同窝仔相比更大并且具有增加的基因组DNA（gDNA）水平。 此外，我们发现cdk 5-/-小鼠胚胎成纤维细胞（MEFs）增殖的速度比野生型MEFs，支持一个新的cdk 5在细胞增殖功能的想法。 因此，我在本申请中的重点是探索我的特定假设，即cdk 5可以抑制细胞周期进程。 我的具体目标是利用cdk 5敲除系统：（i）研究cdk 5-/-小鼠胚胎大小的增加是否是由于细胞数量的增加，（ii）确定cdk 5抑制的细胞周期的特定阶段，（iii）研究cdk 5可能抑制细胞周期的分子机制。 了解cdk 5是如何控制细胞周期的将进一步推进我们对这一基本细胞过程的认识。