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.

GRWD1 regulates ribosomal protein L23 levels via the ubiquitin-proteasome system.

Abstract: Glutamate-rich WD40 repeat-containing 1 (GRWD1) is a Cdt1-binding protein that promotes mini-chromosome maintenance (MCM) loading through its histone chaperone activity. GRWD1 acts as a tumor-promoting factor by downregulating p53 (also known as TP53) via the RPL11-MDM2-p53 axis. Here, we identified GRWD1-interacting proteins using a proteomics approach and showed that GRWD1 interacts with various proteins involved in transcription, translation, DNA replication and repair, chromatin organization, and ubiquitin-mediated proteolysis. We focused on the ribosomal protein ribosomal protein L23 (RPL23), which positively regulates nucleolar stress responses through MDM2 binding and inhibition, thereby functioning as a tumor suppressor. Overexpression of GRWD1 decreased RPL23 protein levels and stability; this effect was restored upon treatment with the proteasome inhibitor MG132. EDD (also known as UBR5), an E3 ubiquitin ligase that interacts with GRWD1, also downregulated RPL23, and the decrease was further enhanced by co-expression of GRWD1. Conversely, siRNA-mediated GRWD1 knockdown upregulated RPL23. Co-expression of GRWD1 and EDD promoted RPL23 ubiquitylation. These data suggest that GRWD1 acts together with EDD to negatively regulate RPL23 via the ubiquitin-proteasome system. GRWD1 expression reversed the RPL23-mediated inhibition of anchorage-independent growth in cancer cells. Our data suggest that GRWD1-induced RPL23 proteolysis plays a role in downregulation of p53 and tumorigenesis.

Facilitation of fas mediated apoptosis of human chondrocytes by the proteasome inhibitor and actinomycin D.

Abstract: OBJECTIVE: We investigated the susceptibility of chondrocytes to apoptosis induced by anti-Fas and various potentiators, and the relevant signaling pathway. METHODS: Chondrocytes were cultured from cartilages obtained at the time of joint replacement surgery for knee osteoarthritis (OA) or femur neck fracture. Fas receptor ligation was performed with agonistic anti-Fas antibody (clone CH-11) at concentrations ranging from 0.5 to 1.0 micro g/ml. Mitogen activated protein kinase inhibitors SB203580 and PD98059, cycloheximide, bisindolylmaleimide, actinomycin D, or MG132 were added with anti-Fas to facilitate cell death. Chondrocyte surface expression of Fas was analyzed by FACS, and the expression of apoptosis related proteins analyzed by Western blot. RESULTS: Cell death increased upon coculture with 0.5 micro g/ml of anti-Fas and 0.2 micro g/ml of actinomycin D or 20 micro M MG132. Apoptosis potentiated by actinomycin D or MG132 was effectively inhibited by caspase inhibitors, implicating the involvement of the caspase cascade in chondrocyte apoptosis. Compared with untreated cells or actinomycin D treated cells, cells treated with MG132 showed distinct shifts in the distribution of surface Fas fluorescence. Although concentrations of Bcl-2, Bax, FLICE inhibitory protein (FLIP), and Fas ligand were unaffected by MG132 or actinomycin D, both treatments led to a significant increase of p53. The expression of the p53 response proteins, MDM2 and p21, was elevated in MG132 treated chondrocytes. CONCLUSION: Our results suggest that chondrocytes can be rendered sensitive to anti-Fas mediated apoptosis by the proteasome inhibitor MG132 and the transcription inhibitor actinomycin D. MG132 and actinomycin D show different characteristics in terms of apoptosis signaling.

Apoptosis meets proteasome, an invaluable therapeutic target of anticancer drugs.

Abstract: This report reviews the current status of extensive efforts directed towards the interpretation of crosstalk between apoptosis and proteasome to understanding the molecular mechanism of anticancer agents targeting proteasome, with particular focus on MG132 and PS-341. The discovery that all cancer cells have retained the apoptotic death program has offered to the researchers new biochemical targets to design anticancer drugs. Moreover, the demonstration that proteasome inhibition induces apoptosis and sensitizes cancer cells to traditional tumoricidal agents has proposed the proteasome as an attractive target for development of new anticancer drugs. Since then, a number of both naturally occurring and synthetic inhibitors of the proteasome have been identified. The best characterized and most widely used inhibitors of the proteasome are the peptide aldehydes; among these MG132, due to its broad spectrum of action, low cost and rapid reversibility of action, still remains the first choice to study proteasome function in cell and tissue cultures. Recently, a very potent new class of selective and reversible proteasome inhibitors which contains an inhibitory boronate group has been described. PS-341 represent the first of this promising class of agents that could have application in cancer therapy and it is the only that has progressed to clinical trials.

Induced degradation of Tat by nucleocapsid (NC) via the proteasome pathway and its effect on HIV transcription.

Abstract: Human Immunodeficiency Virus type 1 (HIV-1) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS). HIV-1 Tat protein upregulates transcriptional transactivation. The nucleocapsid protein NC of HIV-1 is a component of virion and plays a key role in genome packaging. Herein, we have demonstrated the interaction between NC and Tat by means of a yeast two-hybrid assay, GST pull-down analysis, co-immunoprecipitation and subcellular colocalization analysis. We observed that the level of Tat was significantly reduced in the presence of NC. But NC did not affect mRNA expression level of Tat. The level of Tat in the presence of NC was increased by treating cells with a proteasome inhibitor, MG132. The ubiquitination state of Tat was not seen to increase in the presence of NC, suggesting the proteasomal degradation was independent of ubiquitination. Lowered level of Tat in the presence of NC led to a decrease in Tat-mediated transcriptional transactivation.