Function of Atg6 and autophagy in growth control

描述（由申请人提供）：自噬是一种保守的分解代谢过程，用于将细胞质物质递送至溶酶体进行降解，并与癌症和其他疾病有关。自噬基因beclin 1的分子改变与人类癌症有关，对小鼠的研究表明，beclin 1功能下降会导致上皮和造血系统恶性肿瘤的急剧增加。Beclin 1（果蝇中的Atg 6）是进化上保守的Vps 34/III类磷脂酰肌醇3（PI 3）激酶复合物的核心组分，其调节PI 3磷酸（PI 3 P）脂质的形成。虽然Vps 34复合物调节自噬，但PI 3 P在多个囊泡隔室中的功能表明beclin 1/Atg 6的肿瘤抑制功能可能比单独调节自噬更复杂。与beclin 1突变小鼠相似，我们的数据表明果蝇beclin 1（Atg 6）无效突变的动物具有增加的造血细胞，导致血细胞肿瘤。值得注意的是，眼和卵巢滤泡上皮细胞的Atg 6突变克隆具有超过野生型细胞邻居的生长优势，而Vps 34或必需自噬基因Atg 1突变的细胞不具有这种优势.这些结果表明，Atg 6和Vps 34突变体细胞之间存在显着差异，即使这些基因被认为是编码所有PI 3 P调节复合物的核心成分。我们的数据还表明，对beclin 1表型的解释可能过于简化了这种肿瘤抑制因子的功能。因此，我们的假设是Atg 6表型是由改变引起的，而不仅仅是自噬。我们的目标是利用果蝇遗传学的优势来确定Atg 6如何影响细胞和组织的生长。在此，我们建议：（1）确定Atg 6突变细胞缺陷，（2）研究Atg 6、Ref（2）P/p62、NF-kB和组织过度生长之间的遗传关系，和（3）表征参与Atg 6调节的组织过度生长的新因子和途径。Atg 6/Beclin 1和Vps 34调节复合物在所有正常细胞和癌症中的重要性说明了这些研究的意义。

DESCRIPTION (provided by applicant): Autophagy is a conserved catabolic process that is used to deliver cytoplasmic material to the lysosome for degradation, and has been implicated in cancer and other disorders. Molecular alterations in the autophagy gene beclin1 are associated with human cancers, and studies in mice have shown that decreased beclin1 function causes dramatic increase in epithelial and hematopoietic malignancies. Beclin1 (Atg6 in flies) is a core component of the evolutionarily conserved Vps34/class III phosphatidylinositol 3 (PI3) kinase complex that regulates the formation of PI3 phosphate (PI3P) lipids. Although the Vps34 complex regulates autophagy, the function of PI3P in multiple vesicle compartments indicates that the tumor suppressor function of beclin1/Atg6 may be more complex than through the regulation of autophagy alone. Similar to beclin1 mutant mice, our data indicate that animals with null mutations in Drosophila beclin1 (Atg6) possess increased hematopoietic cells resulting in blood cell tumors. Significantly, Atg6 mutant clones of eye and ovarian follicle epithelial cells possess a growth advantage over wild- type cell neighbors that is not shared by cells with mutations in either Vps34 or the essential autophagy gene Atg1. These results indicate that significant differences exist between Atg6 and Vps34 mutant cells even though these genes are thought to encode core components of all PI3P regulatory complexes. Our data also suggest that the interpretation of beclin1 phenotypes likely over-simplify the function of this tumor suppressor. Therefore, our hypothesis is that Atg6 phenotypes are caused by alteration of more than autophagy alone. Our goal is to use the strength of Drosophila genetics to determine how Atg6 influences cell and tissue growth. Here we propose to: (1) determine Atg6 mutant cellular defects, (2) investigate the genetic relationship between Atg6, Ref(2)P/p62, NF-kB and tissue overgrowth, and (3) characterize novel factors and pathways that are involved in Atg6-regulated tissue overgrowth. The importance of Atg6/Beclin1 and the Vps34 regulatory complex in all normal cells and in cancer illustrate the significance of these studies.