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，细胞质组分被隔离到双膜囊泡（自噬体）中并被递送到溶酶体进行降解和再循环。这一过程越来越被认为是细胞生存、分化和发育的关键，并且在人类疾病（包括癌症）中经常被错误调节。虽然已经推测自噬可能既有益于又阻碍肿瘤的发展/进展，但最近的数据表明自噬主要用作肿瘤抑制途径。然而，尽管其重要性，自噬在肿瘤抑制中发挥作用的机制在很大程度上仍不确定。该研究旨在研究自噬如何有助于肿瘤抑制以及其缺陷如何导致恶性肿瘤，特别关注一种新型自噬UVRAG基因，该基因在人类癌症中以高频率发生单等位基因突变。我们的初步研究有UIKO的发现，我们推测UVRAG是一种新的自噬性肿瘤抑制因子，它与Beclin 1和HOPS复合物协同激活自噬，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于详细定义UVRAG在自噬体形成（Aim 1）和自噬体成熟（Aim 2）中的双重作用及其在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自噬调控网络的新观点，还将为癌症控制提出新的策略。 公共卫生相关性：许多研究揭示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，但自噬是否抑制肿瘤发生或促进肿瘤生长仍不清楚和有争议。该研究的挑战是研究肿瘤发展中自噬的分子基础，特别关注一种新型自噬肿瘤抑制剂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.