A metabolic role for PML in tumor suppression

描述（由申请人提供）：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丢失在肥胖、糖尿病和癌症发病中的后果。本研究的相关性在于PML可能被用作代谢性疾病的标志物和治疗靶点。多年来，我们已经克隆，表征和鉴定了PML，作为一种经常在血液和实体癌中丢失的肿瘤抑制因子。PML通过调控衰老、细胞凋亡和新生血管生成发挥抑瘤作用。令人惊讶的是，对PML缺陷小鼠和细胞代谢状态的详细分析揭示了PML在代谢调节中的新作用，表明PML缺失导致能量来源利用改变，禁食反应缺陷和脂肪酸氧化减少。初步数据表明，PML是AMPK适当激活和小鼠对降糖药二甲双胍反应所必需的。此外，PML的细胞质定位在能量剥夺时增加，这表明PML的功能是根据能量需求调节的。癌症基因直接调节代谢过程的概念得到了最近在代谢和癌症的十字路口发现的肿瘤抑制因子和癌基因的支持，如p53和Myc。因此，PML的代谢功能变得非常有吸引力，不仅在代谢疾病本身，而且在癌症易感性的背景下。这一应用是基于细胞质中的PML是细胞正常代谢功能所必需的假设，反过来，PML充分的代谢调节是其肿瘤抑制活性的关键组成部分。我们将以以下具体目的来解决这一假设：(1)明确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况；(2)评估PML调控AMPK的分子机制以及PML丢失对代谢途径的影响；(3)确定PML在细胞质中的调节和代谢功能；(4)研究PML代谢功能对体内肿瘤抑制活性的影响。

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.