MOUSE MODELS FOR PRB GROWTH CONTROL VIA E2F/DP ACTION

视网膜母细胞瘤肿瘤抑制因子（pRB）是一种重要的细胞周期调节因子 参与或脱离细胞周期机制， 刺激或抑制生长、存活和 分化我们广泛的长期目标是了解pRB如何 控制着正常的发育、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 游离E2 F/DP转录活性，其通常是细胞 周期进展。然而，不断增长的pRB相互作用者名单 （>40）表明，除了E2 F/DP转录外， 这些因素可能是pRB控制的下游效应物。因此，它将 理解pRB相互作用者的实际子集是至关重要的 pRB在体内的下游效应物。为了定义生理上的 E2 F-1/DP-1异二聚体转录因子的功能， 为了确定它是否是pRB在体内作用的下游效应物，我们 通过敲除E2 F-1或DP-1基因， 鼠标技术E2 F-1或DP-1的完全不同的表型 突变小鼠（肿瘤和组织萎缩与胚胎致死率） 证明在体内异二聚体的任何一半具有离散的 时间和空间窗口，在这些窗口中， 整个动物。此外，我们最近证明E2 F-1是一种真正的 pRB的下游效应子，因为E2 F-1的缺失干扰内分泌 Rb（+/-）x E2 F-1缺陷型细胞中pRB缺失诱导的肿瘤发生 动物通过了解这些组织的机制- 具体和时间上不同的表型，我们将定位于 控制这些疾病的发展。 提出了以下具体目标，以了解E2 F/DP如何 转录因子作为分子开关（基因激活与 抑制）正确解释和执行来自pRB的命令， 整体动物：（1）了解易感组织如何退化 或在E2 F-1缺陷小鼠中发生肿瘤，（2）为了确定如何损失 DP-1的丢失导致胚胎死亡，（3）为了确定DP-1的丢失是否导致胚胎死亡， E2 F-1干扰内分泌肿瘤的发生或进展 在Rb（+/-）小鼠中，并确定E2 F-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.