A BETA-LACTONE RELATED TO LACTACYSTIN INDUCES NEURITE OUTGROWTH IN A NEUROBLASTOMA CELL-LINE AND INHIBITS CELL-CYCLE PROGRESSION IN AN OSTEOSARCOMA CELL-LINE

被引:220
作者
FENTEANY, G
STANDAERT, RF
REICHARD, GA
COREY, EJ
SCHREIBER, SL
机构
[1] Department of Chemistry, Harvard University, Cambridge
关键词
D O I
10.1073/pnas.91.8.3358
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Lactacystin, a microbial natural product, induces neurite outgrowth in Neuro 2A mouse neuroblastoma cells and inhibits progression of synchronized Neuro 2A cells and MG-63 human osteosarcoma cells beyond the G1 phase of the cell cycle. A related beta-lactone, clasto-lactacystin beta-lactone, formally the product of elimination of N-acetylcysteine from lactacystin, is also active, whereas the corresponding clasto-lactacystin dihydroxy acid is completely inactive. Structural analogs of lactacystin altered only in the N-acetylcysteine moiety are active, while structural or stereochemical modifications of the gamma-lactam ring or the hydroxyisobutyl group lead to partial or complete loss of activity. The inactive compounds do not antagonize the effects of lactacystin in either neurite outgrowth or cell cycle progression assays. The response to lactacystin involves induction of a predominantly bipolar morphology that is maximal 16-32 h after treatment and is distinct from the response to several other treatments that result in morphological differentiation. Neurite outgrowth in response to lactacystin appears to be dependent upon microtubule assembly, actin polymerization, and de novo protein synthesis. The observed structure-activity relationships suggest that lactacystin and its related beta-lactone may act via acylation of one or more relevant target molecule(s) in the cell.
引用
收藏
页码:3358 / 3362
页数:5
相关论文
共 25 条