The RB Gene Family in Cancer Initiation

描述（由申请人提供）：视网膜母细胞瘤（RB）基因是人类癌症的有效抑制基因。虽然RB被认为在细胞周期中具有多种功能，但RB对其肿瘤抑制活性至关重要的具体功能仍不清楚。我们建议测试RB及其两个相关家族成员p107和p130通过控制细胞周期的GO和G1期之间的过渡在体内预防癌症发生中发挥关键作用的想法。具体而言，我们假设RB家族功能的急性体细胞丧失导致关键细胞群中细胞周期退出（G1->GO）和细胞周期再进入（GO->G1）的缺陷，并且这些缺陷可能导致肿瘤发生的开始。我们将使用RB家族基因的种系和条件突变组合的小鼠模型来测试我们的假设。这种小鼠遗传学方法将使我们能够确定RB家族基因在空间和时间定义的细胞群中的作用。这些小鼠模型也将使我们能够在体内重现人类癌症的早期阶段。第一个特定目标的研究将描述RB家族基因在胚胎发育过程中细胞周期退出中的功能。RB患者早在胎儿阶段就发生视网膜母细胞瘤，这是一种视网膜神经肿瘤。我们将把我们的研究重点放在神经祖细胞上，以探讨RB家族功能丧失对细胞周期退出和分化缺陷导致癌症发生的后果。第二个特定目标的研究将确定RB家族蛋白是否是维持体内分化所必需的。具体而言，我们将研究RB家族基因功能急性丧失对体内分化肝细胞重新进入细胞周期的后果。这些研究对于确定某些终末分化细胞是否可能是癌症的起源非常重要。在第三个具体目标的研究将结合联合收割机分子方法和RNA干扰在体内，以了解细胞周期重新进入后，在体内RB家族功能丧失的分子机制。我们将集中研究RB家族突变肝细胞中细胞周期重入的候选介质，包括E2 F转录激活因子和Id 2转录抑制因子。了解RB家族肿瘤抑制因子在体内丢失的分子基础和细胞后果将为癌症起始机制提供重要和新颖的见解。这些研究将进一步为人类癌症早期阶段的检测和治疗提供基础。

DESCRIPTION (provided by applicant): The retinoblastoma (RB) gene is a potent suppressor of human cancers. While RB is thought to have multiple functions during the cell cycle, the specific functions of RB that are critical for its tumor suppression activity are still unclear. We propose to test the idea that RB and its two related family members p107 and p130 play a pivotal role in preventing cancer initiation in vivo by controlling the transition between the GO and G1 phase of the cell cycle. Specifically, we hypothesize that the acute somatic loss of RB family function leads to defects in both cell cycle exit (G1->GO) and cell cycle re-entry (GO->G1) in critical cell populations, and that these defects may result in the initiation of tumorigenesis. We will test our hypothesis using mouse models with combinations of germline and conditional mutations of RB family genes. This mouse genetic approach will enable us to determine the role of RB family genes in spatially and temporally-defined cell populations. These mouse models will also allow us to recapitulate in vivo the early stages of cancer in humans. Studies in the first Specific Aim will characterize the function of RB family genes in cell cycle exit during embryonic development. RB patients develop retinoblastomas, which are retinal neural tumors, as early as the fetal stage. We will focus our studies on neural progenitors to explore the consequences of loss of RB family function on cell cycle exit and differentiation defects leading to cancer initiation. Studies in the second Specific Aim will determine if the RB family proteins are required for maintenance of differentiation in vivo. Specifically, we will investigate the consequences of acute loss of function of RB family genes on cell cycle re-entry of differentiated hepatocytes in vivo. These studies will be important to determine if some terminally differentiated cells may be at the origin of cancer. Studies in the third Specific Aim will combine molecular approaches and RNA interference in vivo to understand the molecular mechanisms underlying cell cycle re-entry upon loss of RB family function in vivo. We will focus our studies on candidate mediators of cell cycle re-entry in RB family mutant hepatocytes, including the E2F transcriptional activator and the Id2 transcriptional repressor. Understanding the molecular bases and the cellular consequences of the loss of RB family tumor suppressors in vivo will give important and novel insights into the mechanisms of cancer initiation. These studies will further provide the foundation for the detection and treatment of early stages of human cancer.