Role of UVRAG-mediated Autophagy in Tumor Suppression

描述(申请人提供)：自噬(希腊语，‘自噬’)是一种进化上保守的动态平衡过程，通过这种过程，细胞质成分被隔离到双膜小泡(自噬小体)中，并被输送到溶酶体进行降解和循环。这一过程越来越被认为是细胞生存、分化和发育所必需的，在包括癌症在内的人类疾病中经常被错误调控。虽然有人推测自噬可能有益于和阻碍肿瘤的发展/进展，但最近的数据表明，自噬主要是作为一种肿瘤抑制途径。然而，尽管自噬很重要，但自噬在肿瘤抑制中的作用机制在很大程度上仍然不确定。这项拟议的研究旨在调查自噬如何有助于肿瘤抑制及其缺陷如何导致恶性肿瘤，特别是一种新的自噬UVRAG基因，该基因在人类癌症中以单等位基因的高频率突变。我们的初步研究有UIKO的发现，我们假设UVRAG是一种新的自噬肿瘤抑制因子，它与Beclin1和HOPS复合体合作，激活自噬并抑制肿瘤的发展。遗传学、生物化学和细胞生物学研究将主要集中于从机制上详细确定UVRAG在自噬小体形成(AIM 1)和自噬小体成熟(AIM 2)中的双重作用，以及它们在UVRAG肿瘤抑制活性(AIM 3)中的功能意义。从这项研究中获得的见解不仅将阐明对自噬调控网络的新观点，而且还将为癌症控制提供新的策略。 与公共卫生相关：许多研究已经阐明了自噬在癌症生物学中的作用，使其成为一个有吸引力的治疗靶点，但自噬是抑制肿瘤发生还是促进肿瘤生长仍不清楚，也存在争议。这项研究的挑战是研究自噬在肿瘤发展中的分子基础，特别关注一种新的自噬肿瘤抑制因子UVRAG，这可能最终有助于建立新的癌症控制治疗策略。

DESCRIPTION (provided by applicant): Autophagy (Greek, 'self-eating') is an evolutionarily conserved homeostatic process by which cytoplasmic components are sequestered into double-membraned vesicles (autophagosome) and delivered to lysosomes for degradation and recycling. This process has been increasingly recognized as essential for cell survival, differentiation, and development, and is often misregulated in human diseases, including cancer. While it has been speculated that autophagy may both benefit and hinder tumor development/progression, recent data indicates that autophagy principally serves as a tumor suppressor pathway. Yet, despite its importance, the mechanisms by which autophagy functions in tumor suppression remain largely undetermined. The proposed study is directed toward investigating how autophagy contributes to tumor suppression and how its defects contribute to malignancy, with a specific focus on a novel autophagic UVRAG gene that is monoallelically mutated at high frequencies in human cancers. Our preliminary studies have UIKO findings, we hypothesize that UVRAG is a novel autophagic tumor suppressor, which cooperates with Beclin1 and the HOPS complex to activate autophagy and inhibit tumor development. Genetic, biochemical and cell biological studies will primarily focus on defining in mechanistic detail the dual roles of UVRAG in autophagosome formation (Aim 1) and autophagosome maturation (Aim 2), and their functional significance in UVRAG tumor suppressor activity (Aim 3). Insights gained from this study will not only illuminate new views on the autophagy regulatory network, but also suggest new strategy for cancer control. PUBLIC HEALTH RELEVANCE: Many studies have shed light on the role of autophagy in cancer biology, making it an attractive therapeutic target, but it remains unclear and controversial whether autophagy suppresses tumorigenesis or favors tumor growth. The challenge of the proposed study is to investigate the molecular basis of autophagy in tumor development with a specific focus on a novel autophagic tumor suppressor UVRAG, which may ultimately contribute to the establishment of new therapeutic strategy for cancer control.