Disease relevance of Z-Leu-leu-leucinal

• Although neither Y. enterocolitica nor TNF-alpha could induce HeLa cell apoptosis alone, TNF-alpha provoked apoptosis when activation of NF-kappaB was inhibited by Yersinia infection or by the proteasome inhibitor MG-132 [1].
• Finally, the adaphostin/MG-132 regimen displayed similar toxicity toward 5 primary AML samples but not normal hematopoietic progenitors (eg, bone marrow CD34+ cells) [2].
• Culture-activated HSCs were stimulated with IL-1beta or tumor necrosis factor alpha (TNFalpha) in the presence or absence of proteasome inhibitors, ALLN or MG-132, or after infection with an adenovirus expressing the IkappaB super-repressor (Ad5IkappaB) or beta-galactosidase (Ad5LacZ) as a control [3].
• Multiple myeloma cells were more sensitive to induction of apoptosis by PS-341 and MG-132 than BzLLLCOCHO [4].
• Here we have investigated the mechanism of apoptosis induced by the proteasome inhibitors MG-132, lactacystin and calpain inhibitor I (ALLN), in the HEK 293 cell line and the ovarian cancer cell lines SKOV3 and OVCAR3 [5].

High impact information on Z-Leu-leu-leucinal

• When NF-kappaB activation was prevented by the proteasome inhibitor MG-132, nonvirulent yersiniae as well as LPS became able to trigger J774A.1 cell apoptosis and inhibition of the TNF-alpha secretion [1].
• We implicate the proteasome at uncoating by completely rescuing the resistant phenotype with the proteasomal inhibitor MG-132 [6].
• The proteasomal inhibitor MG-132 treatment increased levels of ubiquitinated CtBP, which was induced by UV [7].
• Interestingly, enforced Raf or MEK/ERK activation partially diminished adaphostin/MG-132-mediated ROS generation, suggesting the existence of an amplification loop [2].
• Treatment of SV80 cells with the proteasome inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG-132) or geldanamycin, a drug interfering with tumor necrosis factor (TNF)-induced NF-kappaB activation, inhibited TNF-induced upregulation of cFLIP [8].

Chemical compound and disease context of Z-Leu-leu-leucinal

• Collectively, these results demonstrate that the proteasomal inhibitor MG-132 induces dopamine depletion and nigral dopaminergic degeneration in both cell culture and animal models, and suggest that proteasomal dysfunction may promote nigral dopaminergic degeneration in Parkinson's disease [9].

Biological context of Z-Leu-leu-leucinal

• Leukemic CD34(+)/CD38(-) cells displayed a rapid induction of cell death in response to MG-132, whereas normal CD34(+)/CD38(-) cells showed little if any effect [10].
• Prevention of brefeldin A-induced resistance to teniposide by the proteasome inhibitor MG-132: involvement of NF-kappaB activation in drug resistance [11].
• The proteasome inhibitor, MG-132, abolished PMA- but not CGS21680-induced down-regulation of VEGF mRNA [12].
• In this work, we show that BAY 11-7085 but not the proteasome inhibitor MG-132 induced a rapid and sustained phosphorylation of extracellular signal-regulated kinases (ERK1/2) in human articular chondrocytes [13].
• Both TLCK and MG 132 also inhibited iNOS gene expression at the level of mRNA and protein [14].

Anatomical context of Z-Leu-leu-leucinal

• Here, we profile the contributions of the three catalytic activities in multiple myeloma cell lines and compare the specificity and cytotoxicity of the novel proteasome inhibitor BzLLLCOCHO and inhibitors PS-341 (Velcade, bortezomib) and MG-132 [4].
• First, we locally injected MG-132 into the gastrocnemius muscle, and observed the outcome after 24 hours [15].
• Treatment with proteasome inhibitors Z-Leu-Leu-Nva-H (MG-115) or Z-Leu-Leu-Leu-H (MG-132) prevented the accelerated degradation of these mutant receptors, resulting in increased amounts of the mutant receptors in the COS-7 cells [16].
• In the presence of MG-132, LGMD-1C caveolin-3 mutants accumulated within the endoplasmic reticulum and did not reach the plasma membrane [17].
• Western blot and immunological analysis of rat smooth muscle (A7), murine Hepa-1, and human HepG2 cells show that ligand-induced degradation of AHR is blocked when the proteasome is inhibited by MG-132 [18].

Associations of Z-Leu-leu-leucinal with other chemical compounds

• Here we report that immature, core-glycosylated P-gp that is prevented from reaching the cell surface by processing mutations or by proteasome inhibitors such as lactacystin or MG-132 exhibited no detectable drug-stimulated ATPase activity [19].
• Furthermore, we demonstrate that treatment with the proteasome inhibitor MG-132 blocks the activation of NF-kappaB and prevents the development of resistance to VM26 induced by brefeldin A [11].
• Taken together, these results suggest that the pro-apoptotic and anti-apoptotic functions of peptide aldehyde proteasome inhibitors such as MG-132 depend on the concentration of inhibitor utilized and expand the list of stimuli requiring proteasomal activation to induce apoptosis to include viruses [20].
• TLCK and MG 132 inhibited both IL-1beta-induced activation of NFkappaB and degradation of IkappaBalpha by islets and RINm5F cells [14].
• We found that the inhibitor, MG-132, increases amiloride-sensitive trans-epithelial current in Xenopus distal nephron A6 cells [21].

Gene context of Z-Leu-leu-leucinal

• Treatment with the proteasome inhibitor, MG-132, blocked BBS-stimulated NF kappa B DNA binding, and IL-8 and VEGF expression and secretion [22].
• In addition, a mutation of the NF-kappaB site at -200 (pkappaB1 site) completely abolished this IL-1beta- and TNF-alpha-induced hBD-2 promoter activation, whereas NF-kappaB inhibitors (MG-132 and helenalin) strongly suppressed it [23].
• The key role for NF-kappaB in this process was demonstrated by the ability of MG-132 or lactacystin (proteasome inhibitors) to block the enhanced production of MMP-1, COX-2, and PGE(2) [24].
• To test this hypothesis, we treated mdx mice with the well-characterized proteasomal inhibitor MG-132 [15].
• In addition, the expression of phosphorylation-deficient IkappaB and pretreatment with the proteasome inhibitor MG-132 abolished Galpha13- and alpha-thrombin-induced VASP phosphorylation [25].

Analytical, diagnostic and therapeutic context of Z-Leu-leu-leucinal

• Further, ubiquitin-conjugated NFAT5 was not detected in cultured cardiomyocytes treated with MG-132 and/or Dox, as assessed by immunoprecipitation assay, suggesting Dox-induced degradation through ubiquitin-independent proteasome pathway [26].
• However, pretreatment of the cells with the proteasome inhibitor N-cbz-Leu-Leu-leucinal (MG-132, 10 microM) reversed the effects of TNF-alpha on IL-8 release from A549 cells (as determined with an enzyme-linked immunosorbent assay [ELISA]) and on IL-8 gene transcription (as determined with reporter-gene assays) [27].
• Semiquantitative RT-PCR and immunoblotting experiments demonstrate decreased COX-2 expression following treatment with the p38 MAPK inhibitor SB-203580 (25 microM) or the proteosome inhibitor MG-132 (1 microM) [28].
• In vivo, mice that received combined treatments of 2.5 microg/g body weight MG-132 and 30 Gy demonstrated a delay in tumor regrowth in comparison to the 30 Gy control group [29].
• The electrophoretic mobility shift assay (EMSA) with nuclear extracts from MG-132-treated cells revealed formation of a high-molecular-weight RXRbeta-VDR-VDRE complex, which also contained Sug1 [30].

References