MARC Predoctoral Fellowship Program

描述(申请人提供)：自噬过程是蛋白质和其他亚细胞成分的溶酶体降解的复杂分解代谢过程。它对正常的生长控制很重要，在许多癌症中是有缺陷的。Beclin 1基因是第一个被发现参与自噬的哺乳动物基因。在人类散发性乳腺癌、卵巢癌和前列腺癌中，有40%-75%的人发现Beclin 1基因的单等位基因缺失。纯合子的Beclin 1基因敲除小鼠是胚胎致死的，而杂合的Beclin 1基因敲除小鼠会发展成各种肿瘤。这一小鼠遗传结果提供了令人信服的证据，表明自噬在预防肿瘤发生中发挥着重要作用。然而，为什么Beclin 1基因和自噬对肿瘤抑制至关重要，目前尚不清楚。自噬的重新激活可能是一种有效的癌症治疗策略。初步数据表明，在MCF7细胞中模拟结构性磷酸化的Beclin 1突变体的外源表达导致自噬的激活。这个工具将被用来构建细胞和动物模型，以表征重新激活自噬的后果。

DESCRIPTION (provided by applicant): The process of autophagy is a complex catabolic program for lysosomal degradation of proteins and other subcellular constituents. It is important for normal growth control and is defective in a number of cancers. Beclin 1 gene is the first mammalian gene identified involved in autophagy. Mono-allelic deletions of Beclin 1 gene are identified in 40 -75% of human sporadic breast, ovarian and prostate cancers. Homozygous Beclin 1 knockout mice are embryonic lethal, while the heterozygous Beclin 1 knockout mice develop various tumors. This mouse genetic result provides compelling evidence that autophagy plays an important role in preventing tumorigenesis. However, exactly why the Beclin 1 gene and autophagy are critical for tumor suppression remains unknown. The re-activation of autophagy may be an efficient cancer therapeutic strategy. Preliminary data indicates that exogenous expression of the Beclin 1 mutant which mimics constitutive phosphorylation in MCF7 cells results in the activation of autophagy. This tool will be used to construct cellular and animal models to characterize the consequence of re-activating autophagy.