MG132

About: MG132 is a research topic. Over the lifetime, 1499 publications have been published within this topic receiving 56589 citations. The topic is also known as: MG132 & Z-Leu-leu-leu-al.

FoxM1 knockdown sensitizes human cancer cells to proteasome inhibitor-induced apoptosis but not to autophagy

Abstract: Apoptosis has been widely accepted as the primary mechanism of drug-induced cell death. Recently, a second type of cell death pathway has been demonstrated: autophagy, also called programmed type II cell death. Autophagy is a highly regulated process, by which selected components of a cell are degraded. It primarily functions as a cell survival mechanism under stress. However, persistent stress can also promote extensive autophagy leading to cell death. Forkhead box M1 (FoxM1), an oncogenic transcription factor that is abundantly expressed in a wide range of human cancers. Here we evaluated the role of FoxM1 in sensitivity of human cancer cells to proteasome inhibitor-induced apoptosis and autophagy. We found that FoxM1 knockdown sensitized the human cancer cells to apoptotic cell death induced by proteasome inhibitors, such as, MG132, bortezomib and thiostrepton, while it did not affect the levels of autophagy following treatment with these drugs.

Inducible p27 Kip1 expression inhibits proliferation of K562 cells and protects against apoptosis induction by proteasome inhibitors

Abstract: Overexpression of the cyclin-dependent kinase inhibitor p27(Kip1) has been demonstrated to induce cell cycle arrest and apoptosis in various cancer cell lines, but has also been associated with the opposite effect of enhanced survival of tumor cells and increased resistance towards chemotherapeutic treatment. To address the question of how p27(Kip1) expression is related to apoptosis induction, we studied doxycycline-regulated p27(Kip1) expression in K562 erythroleukemia cells. p27(Kip1) expression effectively retards proliferation, but it is not sufficient to induce apoptosis in K562 cells. p27(Kip1)-expressing K562 cells, however, become resistant to apoptosis induction by the proteasome inhibitors PSI, MG132 and epoxomicin, in contrast to wild-type K562 cells that are efficiently killed. Cell cycle arrest in the S phase by aphidicolin, which is not associated with an accumulation of p27(Kip1) protein, did not protect K562 cells against the cytotoxic effect of the proteasome inhibitor PSI. The expression levels of p27(Kip1) thus constitute an important parameter, which decides on the overall sensitivity of cells against the cytotoxic effect of proteasome inhibitors.

Preventive Effect of a Proteasome Inhibitor on the Formation of Accelerated Atherosclerosis in Rabbits With Uremia

Abstract: Inflammation plays a central role in the pathogenesis of atherosclerosis. This study investigated whether the proteasome inhibitor has the same preventive effect on the formation of accelerated atherosclerosis in rabbits with uremia compared with a NF-kappaB inhibitor. New Zealand white rabbits were subjected to five-sixths nephrectomy (chronic renal failure [CRF]) or to a sham operation. Rats in each group were randomly assigned into three subgroups (n = 24 in each group) and treated with repeated intramuscular injections of proteasome inhibitor MG132 or NF-kappaB inhibitor PDTC for a specified period. Compared with sham rabbits, CRF rabbits displayed typical atherosclerotic changes (endothelial cell damage, intimal thickens, and appearance of foam cells). CRF rabbits had significantly higher levels of proteasome activity, NF-kappaB mRNA, protein, and DNA binding activity as well as tumor necrosis factor-a and proliferative cell nuclear antigen protein expression in aortic wall cells. CRF rabbits also showed lower levels of IkappaBalpha. Compared with CRF rabbits, CRF rabbits treatment with proteasome inhibitor MG132 showed restoration of IkappaBalpha mRNA and protein expression and decreased NF-kappaB DNA binding activity and tumor necrosis factor-a expression. Treatment with either proteasome inhibitor MG132 or NF-kappaB inhibitor PDTC could reverse these pathologic changes in the aortic wall cells of CRF rabbits. A comparison between the inhibitory effects of the two treatments revealed no statistical difference. These results suggest that ubiquitin-proteasome activation play a pivotal role in the pathogenesis of uremia-accelerated atherosclerosis. The ubiquitin-proteasome signaling pathway in aortic cells may therefore be an important target for preventing uremia-accelerated atherosclerosis.

Human Immunodeficiency Virus Type 1 Vpr Modulates Cellular Expression of UNG2 via a Negative Transcriptional Effect

Abstract: It was recently reported that human immunodeficiency virus type 1 (HIV-1) Vpr induced the proteasomal degradation of the nuclear UNG2 enzyme for efficient virus replication. We confirm here that HIV-1 infection and Vpr expression reduce the level of endogenous UNG2, but this effect is not reverted by treatment with the proteasome inhibitor MG132. Moreover, this reduction is not mediated by Vpr binding to UNG2 and is independent of the Vpr-induced G2 arrest. Finally, we show that Vpr influences the UNG2 promoter without affecting UNG1 gene expression. These data indicate that the Vpr-induced decrease of UNG2 level is mainly related to a transcriptional effect.