Kinetic Analysis of Myc-induced carcinogenesis in vivo

Myc 诱导体内致癌的动力学分析

• 批准号: 6700732
• 负责人: GERARD IAN EVAN
• 金额: $ 33.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6700732
• 关键词: apoptosis; biological signal transduction; carcinogenesis; genetically modified animals; laboratory mouse; molecular oncology; neoplasm /cancer remission /regression; oncoproteins; pancreatic islets; pathologic process; posttranslational modifications; tumor suppressor proteins

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.

描述(申请人提供)：c-Myc癌蛋白的表达在许多人类癌症中被解除调控或升高。令人惊讶的发现是，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，这增加了这样一种可能性，即细胞凋亡可能是一种内在的肿瘤抑制功能，必须在出现任何肿瘤之前被覆盖。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躯体环境之间微妙的、特定于谱系的相互作用决定的，这些相互作用在体外不能充分复制。不幸的是，Myc诱导的细胞凋亡是如此短暂，以至于在组织特异性Myc表达贯穿个体发育的转基因Myc模型中还不可能直接观察到它。因此，我们只能从观察到的Myc和抗凋亡病变之间的致癌协同作用来推断Myc诱导的细胞凋亡在肿瘤抑制中的作用。为了直接评估Myc诱导的细胞凋亡在Myc诱导的肿瘤发生中的影响，我们建立了一种独特的转基因Myc模型，在该模型中，c-Myc蛋白的可逆切换形式已靶向于胰腺的β细胞。成人β细胞中Myc的急性激活触发了β细胞群体的快速、同步和大规模退化，从而导致糖尿病的急性发作。相反，通过表达凋亡抑制因子Bclxl抑制β细胞的凋亡，将Myc的作用转化为一种有效的多效性肿瘤诱导剂。在这项提案中，我们将验证我们的可切换的β细胞Myc-ER(TM)模型，并确定Myc诱导的凋亡在限制β细胞肿瘤发生中的作用(Aim1)。几种不同的效应分子参与了Myc诱导的细胞凋亡，包括ARF/P53肿瘤抑制通路，通过Fas/Trail/TNFR死亡受体的信号转导，以及生存因子和Bcl2/Bax家族成员对线粒体状态的调节。在目标2中，我们将定义每个效应系统在Myc诱导的细胞凋亡中的作用，并确定它们在Myc诱导的肿瘤发生中的消融后果。Myc失活后，MYC诱导的β细胞肿瘤迅速且完全消退。我们将利用这一现象来确定Myc在维持β细胞肿瘤中的机制要求，以及Myc失活触发肿瘤消退的机制。