A metabolic role for PML in tumor suppression

描述(申请人提供)：本提案旨在描述肿瘤抑制蛋白PML在代谢过程调节中的作用，以及PML缺失在肥胖、糖尿病和癌症发病机制中的后果。这项研究的相关性在于PML可能被用作代谢性疾病的标记物和治疗目标。多年来，我们一直在克隆、鉴定和鉴定PML，作为一种肿瘤抑制因子，经常在血液和实体癌中失血。PML通过调节衰老、细胞凋亡和新生血管生成发挥其肿瘤抑制作用。令人惊讶的是，对PML缺陷小鼠和细胞的代谢状态的详细分析揭示了PML在新陈代谢调节中的新角色，这表明PML缺失导致能源利用改变，对禁食的反应缺陷，并减少脂肪酸氧化。初步数据显示，PML是适当激活AMPK所必需的，也是小鼠对抗糖尿病药物二甲双胍的反应所必需的。此外，能量剥夺后，PML的细胞质定位增加，提示PML功能受能量需求的调节。肿瘤基因直接调节代谢过程的概念已被最近发现的肿瘤抑制基因和处于代谢和癌症十字路口的癌基因所支持，如P53和Myc。因此，PML的代谢功能变得非常有吸引力，不仅在代谢性疾病本身方面，而且在癌症易感性方面也是如此。这一应用是基于这样的假设，即细胞质中的PML是细胞正常代谢功能所必需的，反过来，PML充分的代谢调节是其肿瘤抑制活性的关键成分。我们将针对这一假说提出以下具体目标：(1)确定PML在营养适应中的作用并分析PML在肥胖和糖尿病患者中的状态；(2)评估PML调节AMPK的分子机制以及PML丢失在代谢途径中的后果；(3)确定PML在细胞质中的调节和代谢功能；以及(4)研究PML代谢功能对其体内肿瘤抑制活性的影响。 公共卫生相关性：到目前为止，癌症、糖尿病和肥胖症是西方世界的流行病。它们的发展是相互交织的，因为参与这些代谢紊乱发生的分子途径也与癌症的发展有关。令人兴奋的初步发现表明，PML肿瘤抑制因子不仅可以对抗癌症，还可以对抗这些代谢综合征。这项提案概述了一个研究PML这一新功能的实验计划，具有重要的治疗意义。

DESCRIPTION (provided by applicant): This proposal aims to characterize the role of the tumor suppressor protein PML in the regulation of metabolic processes, and the consequences of PML-loss in obesity, diabetes and cancer pathogenesis. The relevance of this study relies in the possible utilization of PML as a marker of metabolic diseases and target for therapy. We have cloned, characterized and identified PML, throughout the years, as a tumor suppressor frequently loss in blood and solid cancers. PML exerts its tumor suppressive activity through the regulation of senescence, apoptosis and neoangiogenesis. Surprisingly, a detailed analysis of the metabolic status of Pml-deficient mice and cells has unveiled a novel role for PML in the regulation of metabolism, which shows that Pml-loss results in altered energy source utilization, defective response to fasting, and reduced fatty acid oxidation. Preliminary data show that PML is required for proper AMPK activation, and for the response of mice to the antidiabetic drug Metformin. Additionally, cytoplasmic PML localization increases upon energy deprivation, thus suggesting that PML function is modulated according to the demand of energy. The notion of cancer genes directly regulating metabolic processes has been supported by the recent identification of tumor suppressors and oncogenes at the crossroad of metabolism and cancer, such as p53 and Myc. Hence, a metabolic function for PML becomes extremely attractive, not only in terms of metabolic diseases per se, but also in the context of cancer susceptibility. This application is based on the hypothesis that PML in the cytoplasm is required for the proper metabolic function of the cell and that, in turn, adequate metabolic regulation by PML is a key component for its tumor suppressive activity. We will address this hypothesis with the following specific aims: (1) To define the role of PML in nutrient adaptation and analyze the status of PML in obese and diabetic patients; (2) to assess the molecular mechanism of AMPK regulation by PML and the consequences of Pml-loss in metabolic pathways; (3) to ascertain the regulation and metabolic function of PML in the cytoplasm and (4) to study the implications of PML metabolic function on in its tumor suppressive activity in vivo. PUBLIC HEALTH RELEVANCE: Cancer, diabetes and obesity are by now epidemic disorders in the occidental world. Their development is intertwined because molecular pathways that are involved in the genesis of these metabolic disorders have been also implicated in cancer development. Exciting preliminary findings indicate that the PML tumor suppressor opposes cancer but also these metabolic syndromes. This proposal outlines an experimental program to study this novel function of PML with important therapeutic implications.