G1 Cell Cycle in Tumorigenesis and Senescence

描述(由申请人提供)： 这个项目的目的是加深我们对细胞周期从G1期到S期的调控机制的理解，并确定特定的癌蛋白(即突变的CDK4、E1a和MDM2)和潜在的肿瘤抑制蛋白(p130和p107)如何改变这些关键的调控途径。在项目1中，雷迪博士利用转基因小鼠模型系统，计划确定细胞周期蛋白依赖性激酶4(CDK4)中的肿瘤衍生突变如何改变G1到S的进程，并在体外介导细胞衰老的逃逸，并促进体内肿瘤的形成。在项目2中，Grana博士的目标是定义当细胞通过细胞周期的G1晚期和S阶段时发生的p130磷酸化事件，这些事件似乎调节p130蛋白的稳定性，导致p130耗尽的机制，以及这些事件在衰老和转化中的生物学意义。最后，在项目3中，海恩斯博士计划描述新的细胞周期控制分子mtBP如何调节G1到S的进程，以及mdm2癌蛋白如何对mtBP功能产生负面影响。该方案还得到三个核心的后勤支持：转基因动物核心(A)、病毒学/细胞培养核心(B)和行政核心(C)。这些核心将是成功完成所有研究项目的关键。在该计划项目下提出的研究将使科学界更好地了解调控哺乳动物细胞中G1/S进展的机制，以及特定癌基因单独激活或与此途径中的肿瘤抑制基因失活一起导致肿瘤发生的方式。

DESCRIPTION (provided by applicant): The goal of this program is to further our understanding of the mechanisms that regulate the progression of cells from the G1 phase to the S phase of the cell cycle and to determine how specific oncoproteins (i.e. mutant CDK4, E1A and MDM2) and potential tumor suppressor proteins (p130 and p107) alter these critical regulatory pathways. In Project #1, Dr. Reddy, utilizing a transgenic mouse model system, plans to determine how a tumor-derived mutation in the cyclin-dependent kinase 4 (CDK4) alters G1 to S progression and mediates escape from cellular senescence in vitro and promotes tumorigenesis in vivo. In Project #2, Dr. Grana aims to define p130 phosphorylation events that occur as cells pass through late G1 and S phases of the cell cycle that appear to regulate p130 protein stability, the mechanisms that result in p130 depletion, and the biological significance of these events in senescence and transformation. Finally, in Project 3, Dr. Haines plans to characterize how the novel cell cycle control molecule MTBP regulates G1 to S progression and how the MDM2 oncoprotein negatively affects MTBP function. The program is also logistically supported by three Cores; a Transgenic Animal Core (A), a Virology/Cell Culture Core (B) and an Administrative Core (C). The cores will be essential for the successful completion of all research projects. The studies proposed under this Program Project should provide the scientific community with a better understanding of the mechanisms that regulate G1/S progression in mammalian cells and how activation of particular oncogenes alone or in combination with inactivation of tumor suppressor genes from this pathway leads to tumorigenesis.