Kinetic Analysis of Myc-induced carcinogenesis in vivo

描述（由申请人提供）：c-Myc癌蛋白的表达在许多人类癌症中不受调节或升高。令人惊讶的发现，Myc可以诱导细胞凋亡，特别是在受到生存因子、死亡受体信号或基因毒性或其他应激的细胞中，这提高了细胞凋亡可能作为一种内在的肿瘤抑制功能的可能性，这种功能必须在任何肿瘤出现之前被覆盖。Myc在体内任何情况下促进细胞凋亡的倾向都是由细胞与其局部体细胞环境之间微妙的、谱系特异性的相互作用决定的，这种相互作用不能在体外充分复制。不幸的是，Myc诱导的细胞凋亡是如此短暂，以至于不可能在转基因Myc模型中直接观察到它，在转基因Myc模型中，组织特异性Myc表达在整个个体发生过程中都存在。因此，我们只能从观察到的Myc与抗凋亡病变之间的致癌合作中推断Myc诱导的细胞凋亡在肿瘤抑制中的作用。为了直接评估Myc诱导的细胞凋亡对Myc诱导的肿瘤发生的影响，我们建立了一种独特的转基因Myc模型，其中一种可逆切换形式的c-Myc蛋白已被靶向胰腺的β细胞。成人β细胞中Myc的急性激活引发β细胞群的快速、同步和大规模退化，导致糖尿病的急性发作。相反，通过表达凋亡抑制因子Bcl-xL抑制β细胞凋亡可将Myc转化为一种强效的多效肿瘤诱导剂。在这项提议中，我们将验证我们的可切换β细胞Myc-ER（TM）模型，并定义myc诱导的凋亡在限制β细胞肿瘤发生（Aim1）中的作用。几个独立的效应因子与myc诱导的细胞凋亡有关，包括ARF/p53肿瘤抑制通路，通过Fas/Trail/TNFR死亡受体发出信号，以及生存因子和Bcl-2/Bax家族成员对线粒体状态的调节。在目标2中，我们将定义每种效应系统对myc诱导的细胞凋亡的贡献，并确定其消融对myc诱导的肿瘤发生的影响。Myc诱导的β细胞肿瘤在Myc失活后迅速完全消退。我们将利用这一现象来定义Myc在维持β细胞肿瘤中的机制需求，以及Myc失活触发肿瘤消退的机制。

DESCRIPTION (provided by applicant): Expression of the c-Myc oncoprotein is deregulated or elevated in many human cancers. The surprising discovery that Myc can induce apoptosis, particularly in cells subjected to survival factors, death receptor signals or genotoxic or other stress, raised the possibility that apoptosis might serve as an inbuilt tumor suppressive function that must be overridden before any tumors can emerge. The proclivity of Myc to promote apoptosis in any instance in vivo is critically determined by subtle and lineage-specific interactions between the cell and its local somatic environment that cannot be adequately reproduced in vitro. Unfortunately, Myc-induced apoptosis is so ephemeral that it has not proved possible to observe it directly in transgenic Myc models in which tissue-specific Myc expression has been present throughout ontogeny. Consequently, we can only infer a role for Myc-induced apoptosis in tumor suppression from the observed oncogenic cooperation between Myc and anti-apoptotic lesions. To evaluate directly the influence of Myc-induced apoptosis in Myc-induced tumorigenesis we have built a unique transgenic Myc model in which a reversibly switchable form of the c-Myc protein has been targeted to the beta cells of the pancreas. Acute activation of Myc in adult beta cells triggers a rapid, synchronous and wholesale involution of the beta cell population leading to the acute onset of diabetes. In contrast, suppression of beta cell apoptosis by expression of the apoptosis suppressor Bcl-xL transforms the effect of Myc into a potent and pleiotropic tumor inducer. In this proposal we will validate our switchable beta cell Myc-ER(TM) model and define the role of Myc-induced apoptosis in limiting beta cell tumorigenesis (Aim1). Several discrete effectors are implicated in Myc-induced apoptosis, including the ARF/p53 tumor suppressor pathway, signaling through the Fas/Trail/TNFR death receptors and regulation of mitochondrial status by survival factors and members of the Bcl-2/Bax family. In Aim 2 we will define the contribution of each of these effector systems towards Myc-induced apoptosis and determine the consequences of their ablation for Myc-induced tumorigenesis. Myc-induced beta cell tumors rapidly and completely regress following Myc de-activation. We will use this phenomenon to define the mechanistic requirement for Myc in the maintenance of beta cell tumors and the mechanism by which Myc deactivation triggers tumor regression.