Role of UVRAG-mediated Autophagy in Tumor Suppression

描述（由申请人提供）：自噬（希腊语，“自噬”）是一种进化上保守的稳态过程，通过该过程，细胞质成分被隔离到双膜囊泡（自噬体）中，并传递给溶酶体进行降解和再循环。这一过程越来越被认为是细胞存活、分化和发育的必要条件，并且在包括癌症在内的人类疾病中经常被错误调节。据推测，自噬可能有利于和阻碍肿瘤的发展/进展，但最近的数据表明，自噬主要作为肿瘤抑制途径。然而，尽管它很重要，自噬在肿瘤抑制中的作用机制在很大程度上仍不确定。该研究旨在研究自噬如何促进肿瘤抑制及其缺陷如何促进恶性肿瘤，并特别关注一种在人类癌症中高频率发生单等位突变的新型自噬UVRAG基因。我们的前期研究有UIKO的发现，我们假设UVRAG是一种新型的自噬肿瘤抑制因子，它与Beclin1和HOPS复合物共同激活自噬，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在机制细节上定义UVRAG在自噬体形成（Aim 1）和自噬体成熟（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。本研究不仅将阐明自噬调控网络的新观点，也将为癌症控制提供新的策略。

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.