MOUSE MODELS FOR PRB GROWTH CONTROL VIA E2F/DP ACTION

视网膜母细胞瘤肿瘤抑制因子(PRB)是一种关键的细胞周期调节因子 启动或退出细胞周期机制以响应 刺激或抑制信号对生长、生存和 差异化。我们广泛的长期目标是了解公共关系科如何 控制正常的发育、生长和分化过程 以及pRb功能的丧失如何导致这些 分子水平上的病理学。肿瘤抑制的早期模型 预测pRb仅通过结合和抑制抑制生长 正常情况下细胞所需的自由E2F/DP转录活性 循环递增。然而，越来越多的公共关系-互动者名单 (&gt；40)表明除了E2F/DP转录外，还有许多蛋白质 这些因素可能是PRB控制的下游效应者。因此，它将 关键是要了解pRB-相互作用因子的实际子集是什么 活体内pRb的下游效应物。为了定义生理学 E2F-1/DP-1异源二聚体转录因子的功能及TO 确定它是否是体内pRb作用的下游效应器，我们 通过基因敲除创造了缺乏E2F-1或DP-1的突变小鼠 鼠标技术。E2F-1或DP-1的截然不同的表型 突变小鼠(肿瘤和组织萎缩与胚胎致死率相比) 证明在体内，杂二聚体的任何一半都具有离散的 时间窗口和空间窗口，其中它的功能在 整个动物。此外，我们最近证明了E2F-1是一种真正的 由于E2F-1缺失干扰内分泌，pRb的下游效应 Rb(/-)x E2F-1缺陷中pRb缺失引起的肿瘤发生 动物。通过了解这些组织的机制- 特定的和时间上不同的表型，我们将定位于 控制这些疾病在未来的发展。 为了了解E2F/DP如何 转录因子充当分子开关(基因激活与 Repression)正确解释和执行来自PRB的命令 整个动物：(1)了解易感组织如何退化 或在E2F-1缺陷小鼠中发生肿瘤，(2)确定如何丢失 DP-1导致胚胎死亡，(3)确定是否丢失 E2F-1干扰内分泌肿瘤的发生或发展 在RB(/-)小鼠中的表达，并确定E2F-1的缺失如何延长 RB(/-)动物。

The retinoblastoma tumor suppressor (pRB) is a key cell cycle regulator that engages or disengages the cell cycle machinery in response to stimulatory or inhibitory signals for growth, survival and differentiation. Our broad long-term objective is to understand how pRB controls the normal processes of development, growth and differentiation in the whole animal, and how loss of pRB function results in these pathologies at the molecular level. Early models of tumor suppression predicted that pRB suppressed growth solely by binding and repressing free E2F/DP transcriptional activity that is normally required for cell cycle progression. However, the ever-growing list of pRB-interactors (>40) suggests that many proteins beside the E2F/DP transcription factors may serve as downstream effectors of pRB control. Thus, it will be critical to understand what subset of pRB-interactors actually are downstream effectors of pRB in vivo. To define the physiological function of E2F-1/DP-1 heterodimeric transcription factor and to determine whether it is a downstream effector of pRB action in vivo, we have created mutant mice which lack either E2F-1 or DP-1 by knock-out mouse technology. The radically distinct phenotypes of the E2F-1 or DP-1 mutant mice (tumors and tissue atrophy versus embryonic lethality) demonstrate that in vivo either half of the heterodimer has discrete temporal and spatial windows in which its function is critical in the whole animal. Further, we recently demonstrated that E2F-1 is a genuine downstream effector of pRB since loss of E2F-1 interferes with endocrine tumorigenesis induced by loss of pRB in Rb(+/-) x E2F-1 deficient animals. By understanding the mechanisms responsible for these tissue- specific and temporally distinct phenotypes, we will be positioned to control the development of these pathologies in the future. The following specific aims are proposed to understand how E2F/DP transcription factors act as molecular switches (gene activation versus repression) correctly interpreting and executing commands from pRB in the whole animals: (1) To understand how susceptible tissues degenerate or develop tumors in the E2F-1 deficient mice, (2) To determine how loss of DP-1 results in embryonic lethality, (3) To determine whether loss of E2F-1 interferes with the initiation or progression of endocrine tumors in Rb(+/-) mice and to determine how loss of E2F-1 lengthens lifespan of the Rb(+/-) animals.