Function of Atg6 and autophagy in growth control

描述(申请人提供)：自噬是一种保守的分解代谢过程，用于将细胞质物质输送到溶酶体进行降解，并与癌症和其他疾病有关。自噬基因beclin1的分子变化与人类癌症有关，在小鼠身上的研究表明，beclin1功能下降会导致上皮和血液系统恶性肿瘤的急剧增加。Beclin1(果蝇中的Atg6)是进化上保守的Vps34/III类磷脂酰肌醇3(PI3)激酶复合体的核心成分，调节PI3磷酸(PI3P)脂类的形成。尽管Vps34复合体调节自噬，但PI3P在多个囊泡中的功能表明，Beclin1/Atg6的肿瘤抑制功能可能比单独通过自噬调节更为复杂。与Beclin1突变小鼠类似，我们的数据表明，果蝇Beclin1(Atg6)零突变动物的造血细胞增加，导致血细胞肿瘤。值得注意的是，眼部和卵巢滤泡上皮细胞的Atg6突变克隆拥有比野生型细胞邻居更好的生长优势，这是Vps34或基本自噬基因Atg1突变的细胞所不具备的。这些结果表明，Atg6和Vps34突变细胞之间存在显著差异，尽管这些基因被认为编码所有PI3P调节复合体的核心成分。我们的数据还表明，对Beclin1表型的解释可能过度简化了这种肿瘤抑制因子的功能。因此，我们的假设是，Atg6的表型不仅仅是由自噬的改变引起的。我们的目标是利用果蝇遗传学的力量来确定Atg6如何影响细胞和组织生长。在这里，我们建议：(1)确定Atg6突变的细胞缺陷；(2)研究Atg6、Ref(2)P/p62、NF-kB与组织过度生长之间的遗传关系；(3)表征参与Atg6调控的组织过度生长的新因素和新途径。Atg6/Beclin1和Vps34调控复合体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.