Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cell Death Differ. 2013 Feb;20(2):218-25. doi: 10.1038/cdd.2012.110. Epub 2012 Aug 31.
Proteasome inhibitors induce cell death and are used in cancer therapy, but little is known about the relationship between proteasome impairment and cell death under normal physiological conditions. Here, we investigate the relationship between proteasome function and larval salivary gland cell death during development in Drosophila. Drosophila larval salivary gland cells undergo synchronized programmed cell death requiring both caspases and autophagy (Atg) genes during development. Here, we show that ubiquitin proteasome system (UPS) function is reduced during normal salivary gland cell death, and that ectopic proteasome impairment in salivary gland cells leads to early DNA fragmentation and salivary gland condensation in vivo. Shotgun proteomic analyses of purified dying salivary glands identified the UPS as the top category of proteins enriched, suggesting a possible compensatory induction of these factors to maintain proteolysis during cell death. We compared the proteome following ectopic proteasome impairment to the proteome during developmental cell death in salivary gland cells. Proteins that were enriched in both populations of cells were screened for their function in salivary gland degradation using RNAi knockdown. We identified several factors, including trol, a novel gene CG11880, and the cop9 signalsome component cop9 signalsome 6, as required for Drosophila larval salivary gland degradation.
蛋白酶体抑制剂诱导细胞死亡,并被用于癌症治疗,但在正常生理条件下,蛋白酶体损伤与细胞死亡之间的关系知之甚少。在这里,我们研究了在果蝇发育过程中蛋白酶体功能与幼虫唾腺细胞死亡之间的关系。果蝇幼虫唾腺细胞在发育过程中经历同步的程序性细胞死亡,需要半胱天冬酶和自噬(Atg)基因。在这里,我们表明泛素蛋白酶体系统(UPS)功能在正常唾腺细胞死亡过程中降低,并且唾腺细胞中的异位蛋白酶体损伤导致体内早期 DNA 片段化和唾腺浓缩。纯化的死亡唾腺的鸟枪法蛋白质组学分析将 UPS 鉴定为富含的蛋白质的首要类别,表明在细胞死亡过程中可能诱导这些因子的补偿性诱导以维持蛋白水解。我们将异位蛋白酶体损伤后的蛋白质组与唾腺细胞发育性细胞死亡后的蛋白质组进行了比较。使用 RNAi 敲低筛选在这两种细胞群中富集的蛋白质,以研究其在唾腺降解中的功能。我们鉴定了几种因子,包括 trol、一个新的基因 CG11880 和 cop9 信号体成分 cop9 信号体 6,它们是果蝇幼虫唾腺降解所必需的。