The Neuritogenesis Inducer Lactacystin Arrests Cell Cycle at Both G0/G1 and G2 Phases in Neuro 2a Cells

In vivo degradation of N-myc in neuroblastoma cells is mediated by the 26S proteasome

“…Indeed, although some of the biochemical properties of the proteasome are well characterized (Orlowski, 1990;Orlowski et al, 1993), the physiologic functions of this proteinase complex have been di cult to study due to the lack of speci®c inhibitors. Recently, a novel streptomyces metabolite, lactacystin, discovered on the basis of its ability to induce neurite outgrowth in the murine neuroblastoma cell line Neuro-2A (Katagiri et al, 1995;Fenteany et al, 1994;Fenteany and Schreiber, 1996), has emerged as a highly speci®c, irreversible inhibitor of 26S proteasome chymotrypsin-like and trypsin-like activity, without a ecting lysosomal and nonlysosomal cysteine proteases, cathepsin or calpain (Fenteany et al, 1995). The inhibitory e ect of lactacystin on ubiquitin/ATP-dependent degradation of several proteins has been demonstrated both in mammalian cells (Blagosklonny et al, 1996;Bies and Wol , 1997;Oda et al, 1996;Mimnaugh et al, 1996;Lee and Goldberg, 1996; Je ers et al, 1997; Whitesell et al, 1997) and in yeast .…”

Lactacystin, Proteasome Function, and Cell Fate

“…1) was discovered on the basis of its ability to inhibit cell growth and to induce neurite outgrowth in a murine neuroblastoma cell line, Neuro-2a (3). The cytostatic effects of lactacystin are not unique to Neuro-2a cells (4), and lactacystin has been found to inhibit cell cycle progression in both the G 0 /G 1 and G 2 /M phases of the cell cycle (4,5). Lactacystin treatment of Neuro-2a cells results in a predominantly bipolar morphology with two long processes emanating from opposite sides of the cell body, maximal between 16 and 32 h after the start of treatment (4).…”

The role of the ubiquitin-proteasome pathway in apoptosis

“…Early studies evaluating the consequences of inhibition of this function revealed mutations in a ubiquitinactivating enzyme in Chinese hamster ovary cells led to an arrest at G 2 /M, 80 as did yeast mutations which prevented the assembling of ubiquitin chains. 81 Inhibition of the proteasome resulted in cell-cycle arrest at the G 1 /S boundary in Chinese hamster ovary cells 82 as well as in Neuro 2A and MG-63 osteosarcoma cells, 83 while HeLa cells arrested at G 2 /M, 84 and other studies noted cellular arrest at both G 1 /S and G 2 / M. 85 This is by no means a complete review of the effects of proteasome inhibition on progression through the cell cycle, however, which is beyond the scope of this work. The reader is referred to several recent reviews.…”