The Role of Cell Size and G1-phase Cdks in Cell Growth Control

描述（由申请人提供）：g1期周期蛋白依赖激酶（Cdks）是增殖和正常发育所必需的。这些复合物的活性主要受生长因子和有丝分裂原的调节，它们通过诱导g1期细胞周期蛋白的表达来促进增殖。然而，控制g1期细胞周期蛋白的时间、表达水平和活性的机制仍不清楚。因此，我的实验室的广泛和长期目标是识别和剖析控制g1期细胞周期蛋白表达的遗传、分子和生化途径，并确定g1期Cdks在细胞生长控制中的作用。使用酵母作为遗传模型系统，我们已经证明g1期周期蛋白的表达，重要的是，细胞的增殖率，与细胞大小密切相关；与小细胞相比，大细胞更快、更高水平地表达g1期细胞周期蛋白。随后，大细胞比小细胞增殖得快得多。由于g1期Cdks和细胞周期控制的基本机制是高度保守的，我们假设哺乳动物细胞增殖和g1期周期蛋白表达也与细胞大小有关。此外，由于g1期Cdks的过度激活与癌症的发生有关，因此在哺乳动物细胞中，细胞大小、g1期细胞周期蛋白表达和增殖之间的机制联系的论证将具有生物学和临床意义。因此，在本建议中，我们处理三个问题：哺乳动物细胞的增殖速率与细胞大小有关吗？2。g1期细胞周期蛋白的表达与细胞大小有何关系？3。g1期Cdk活性是否将增殖速率与细胞大小联系起来？完成本基金提出的实验将极大地阐明细胞大小、g1期Cdk活性和细胞增殖能力之间的关系。我们提出，利用g1期Cdks将细胞大小与增殖率联系起来是一种重要的生理手段，可以使大型静息细胞（如干细胞）在刺激下快速增殖——这是干细胞特有的重要保守功能。然而，不能适当下调G1期Cdk活性可能是导致癌症的原因之一。这证明了理解g1期Cdks在增殖中的作用至关重要，因为在设计有效的抗癌临床干预措施之前，这种类型的信息是必不可少的。

DESCRIPTION (provided by applicant): G1-phase cyclin dependent kinases (Cdks) are required for proliferation and normal development. The activity of these complexes is modulated predominately by growth factors and mitogens which promote proliferation by inducing the expression of G1-phase cyclins. However, the mechanisms that control the timing, expression levels, and activity of G1-phase cyclins are still not well understood. Thus, the broad and long-term goals of my laboratory are to identify and dissect the genetic, molecular and biochemical pathways that control G1-phase cyclin expression and to determine the role of G1-phase Cdks in cell growth control. Using yeast as a genetic model system, we have demonstrated that G1-phase cyclin expression, and importantly, the proliferation rate of cells, is strongly linked to cell size; large cells express G1-phase cyclins sooner and to higher levels as compared to small cells. Subsequently, large cells proliferate much more rapidly than small cells. Because G1-phase Cdks and the basic mechanisms of cell cycle control are so highly conserved, we hypothesize that mammalian cell proliferation and G1-phase cyclin expression are also linked to cell size. Moreover, since hyper-activation of G1-phase Cdks is implicated in the causation of cancer, the demonstration of a mechanistic link between cell size, G1-phase cyclin expression, and proliferation in mammalian cells will be both biologically and clinically relevant. Therefore, in this proposal, we address three questions: 1. Is proliferation rate of mammalian cells linked to cell size?, 2. How is the expression of G1-phase cyclins linked to cell size?, and 3. Does G1-phase Cdk activity link proliferation rate to cell size? Completion of the experiments proposed in this grant will greatly clarify the relationships between cell size, G1-phase Cdk activity, and the proliferative capacity of cells. We propose that linking cell size to proliferation rate using G1-phase Cdks represents an important physiological means that enables large resting cells (e.g. stem cells) to proliferate rapidly in response to stimuli-an important conserved function specific to stem cells. However, the inability to appropriately down regulate G1 -phase Cdk activity might be a cause of cancer. This exemplifies the critical importance of understanding the role of G1-phase Cdks in proliferation because this type of information is essential before effective anti-cancer clinical interventions can be designed.