The RB Gene Family in Cancer Initiation

描述（由申请人提供）：视网膜母细胞瘤（RB）基因是一种有效的人类癌症抑制因子。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尚不清楚。我们提出验证RB及其两个相关家族成员p107和p130在体内通过控制细胞周期的GO期和G1期之间的过渡在预防癌症发生中发挥关键作用的观点。具体来说，我们假设RB家族功能的急性躯体丧失导致关键细胞群中细胞周期退出（G1->GO）和细胞周期重新进入（GO->G1）的缺陷，这些缺陷可能导致肿瘤发生的开始。我们将使用RB家族基因的生殖系和条件突变组合的小鼠模型来验证我们的假设。这种小鼠遗传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体中的作用。这些小鼠模型也将使我们能够在体内概括人类癌症的早期阶段。第一个特异性目标的研究将描述RB家族基因在胚胎发育过程中细胞周期退出的功能。RB患者早在胎儿期就发展成视网膜母细胞瘤，这是一种视网膜神经肿瘤。我们将重点研究神经祖细胞，探讨RB家族功能缺失对细胞周期退出和分化缺陷导致癌症起始的影响。第二个特异性目标的研究将确定RB家族蛋白是否需要维持体内分化。具体来说，我们将研究RB家族基因急性功能丧失对体内分化肝细胞细胞周期再进入的影响。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将是重要的。第三个专题的研究将结合分子方法和体内RNA干扰来了解体内RB家族功能丧失后细胞周期重新进入的分子机制。我们将重点研究RB家族突变肝细胞细胞周期再进入的候选介质，包括E2F转录激活因子和Id2转录抑制因子。了解RB家族肿瘤抑制因子在体内缺失的分子基础和细胞后果将为癌症发生机制提供重要的新见解。这些研究将进一步为早期人类癌症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.