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Chemical Compound Review

Zlllal     benzylN-[3-methyl-1-[[3- methyl-1-[[(2S)-4...

Synonyms: Zlll-cho, Z-LLL, CHEMBL388078, Lll cpd, LS-172868, ...
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Disease relevance of Z-Leu-leu-leucinal


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


Biological context of Z-Leu-leu-leucinal


Anatomical context of Z-Leu-leu-leucinal


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


  1. Yersinia enterocolitica impairs activation of transcription factor NF-kappaB: involvement in the induction of programmed cell death and in the suppression of the macrophage tumor necrosis factor alpha production. Ruckdeschel, K., Harb, S., Roggenkamp, A., Hornef, M., Zumbihl, R., Köhler, S., Heesemann, J., Rouot, B. J. Exp. Med. (1998) [Pubmed]
  2. The tyrphostin adaphostin interacts synergistically with proteasome inhibitors to induce apoptosis in human leukemia cells through a reactive oxygen species (ROS)-dependent mechanism. Dasmahapatra, G., Rahmani, M., Dent, P., Grant, S. Blood (2006) [Pubmed]
  3. Inhibition of NFkappaB in activated rat hepatic stellate cells by proteasome inhibitors and an IkappaB super-repressor. Hellerbrand, C., Jobin, C., Iimuro, Y., Licato, L., Sartor, R.B., Brenner, D.A. Hepatology (1998) [Pubmed]
  4. Comparative selectivity and specificity of the proteasome inhibitors BzLLLCOCHO, PS-341, and MG-132. Crawford, L.J., Walker, B., Ovaa, H., Chauhan, D., Anderson, K.C., Morris, T.C., Irvine, A.E. Cancer Res. (2006) [Pubmed]
  5. Pro-caspase-3 overexpression sensitises ovarian cancer cells to proteasome inhibitors. Tenev, T., Marani, M., McNeish, I., Lemoine, N.R. Cell Death Differ. (2001) [Pubmed]
  6. Isolation, characterization, and genetic complementation of a cellular mutant resistant to retroviral infection. Agarwal, S., Harada, J., Schreifels, J., Lech, P., Nikolai, B., Yamaguchi, T., Chanda, S.K., Somia, N.V. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. Homeodomain-interacting protein kinase-2 mediates CtBP phosphorylation and degradation in UV-triggered apoptosis. Zhang, Q., Nottke, A., Goodman, R.H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  8. NF-kappaB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling. Kreuz, S., Siegmund, D., Scheurich, P., Wajant, H. Mol. Cell. Biol. (2001) [Pubmed]
  9. Proteasome inhibitor MG-132 induces dopaminergic degeneration in cell culture and animal models. Sun, F., Anantharam, V., Zhang, D., Latchoumycandane, C., Kanthasamy, A., Kanthasamy, A.G. Neurotoxicology (2006) [Pubmed]
  10. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Guzman, M.L., Neering, S.J., Upchurch, D., Grimes, B., Howard, D.S., Rizzieri, D.A., Luger, S.M., Jordan, C.T. Blood (2001) [Pubmed]
  11. Prevention of brefeldin A-induced resistance to teniposide by the proteasome inhibitor MG-132: involvement of NF-kappaB activation in drug resistance. Lin, Z.P., Boller, Y.C., Amer, S.M., Russell, R.L., Pacelli, K.A., Patierno, S.R., Kennedy, K.A. Cancer Res. (1998) [Pubmed]
  12. Distinct protein kinase C isoforms mediate regulation of vascular endothelial growth factor expression by A2A adenosine receptor activation and phorbol esters in pheochromocytoma PC12 cells. Gardner, A.M., Olah, M.E. J. Biol. Chem. (2003) [Pubmed]
  13. 15-deoxy-delta12,14-prostaglandin J2 inhibits Bay 11-7085-induced sustained extracellular signal-regulated kinase phosphorylation and apoptosis in human articular chondrocytes and synovial fibroblasts. Relic, B., Benoit, V., Franchimont, N., Ribbens, C., Kaiser, M.J., Gillet, P., Merville, M.P., Bours, V., Malaise, M.G. J. Biol. Chem. (2004) [Pubmed]
  14. Evidence for involvement of the proteasome complex (26S) and NFkappaB in IL-1beta-induced nitric oxide and prostaglandin production by rat islets and RINm5F cells. Kwon, G., Corbett, J.A., Hauser, S., Hill, J.R., Turk, J., McDaniel, M.L. Diabetes (1998) [Pubmed]
  15. Proteasome inhibitor (MG-132) treatment of mdx mice rescues the expression and membrane localization of dystrophin and dystrophin-associated proteins. Bonuccelli, G., Sotgia, F., Schubert, W., Park, D.S., Frank, P.G., Woodman, S.E., Insabato, L., Cammer, M., Minetti, C., Lisanti, M.P. Am. J. Pathol. (2003) [Pubmed]
  16. Involvement of heat shock protein 90 in the degradation of mutant insulin receptors by the proteasome. Imamura, T., Haruta, T., Takata, Y., Usui, I., Iwata, M., Ishihara, H., Ishiki, M., Ishibashi, O., Ueno, E., Sasaoka, T., Kobayashi, M. J. Biol. Chem. (1998) [Pubmed]
  17. Limb-girdle muscular dystrophy (LGMD-1C) mutants of caveolin-3 undergo ubiquitination and proteasomal degradation. Treatment with proteasomal inhibitors blocks the dominant negative effect of LGMD-1C mutanta and rescues wild-type caveolin-3. Galbiati, F., Volonte, D., Minetti, C., Bregman, D.B., Lisanti, M.P. J. Biol. Chem. (2000) [Pubmed]
  18. Aryl hydrocarbon receptor imported into the nucleus following ligand binding is rapidly degraded via the cytosplasmic proteasome following nuclear export. Davarinos, N.A., Pollenz, R.S. J. Biol. Chem. (1999) [Pubmed]
  19. The human multidrug resistance P-glycoprotein is inactive when its maturation is inhibited: potential for a role in cancer chemotherapy. Loo, T.W., Clarke, D.M. FASEB J. (1999) [Pubmed]
  20. Inhibition versus induction of apoptosis by proteasome inhibitors depends on concentration. Lin, K.I., Baraban, J.M., Ratan, R.R. Cell Death Differ. (1998) [Pubmed]
  21. Enac degradation in A6 cells by the ubiquitin-proteosome proteolytic pathway. Malik, B., Schlanger, L., Al-Khalili, O., Bao, H.F., Yue, G., Price, S.R., Mitch, W.E., Eaton, D.C. J. Biol. Chem. (2001) [Pubmed]
  22. Bombesin stimulates nuclear factor kappa B activation and expression of proangiogenic factors in prostate cancer cells. Levine, L., Lucci, J.A., Pazdrak, B., Cheng, J.Z., Guo, Y.S., Townsend, C.M., Hellmich, M.R. Cancer Res. (2003) [Pubmed]
  23. Modulation of human beta-defensin-2 transcription in pulmonary epithelial cells by lipopolysaccharide-stimulated mononuclear phagocytes via proinflammatory cytokine production. Tsutsumi-Ishii, Y., Nagaoka, I. J. Immunol. (2003) [Pubmed]
  24. Oxidative stress augments the production of matrix metalloproteinase-1, cyclooxygenase-2, and prostaglandin E2 through enhancement of NF-kappa B activity in lipopolysaccharide-activated human primary monocytes. Lu, Y., Wahl, L.M. J. Immunol. (2005) [Pubmed]
  25. A novel mechanism of G protein-dependent phosphorylation of vasodilator-stimulated phosphoprotein. Profirovic, J., Gorovoy, M., Niu, J., Pavlovic, S., Voyno-Yasenetskaya, T. J. Biol. Chem. (2005) [Pubmed]
  26. Degradation of NFAT5, a Transcriptional Regulator of Osmotic Stress-related Genes, Is a Critical Event for Doxorubicin-induced Cytotoxicity in Cardiac Myocytes. Ito, T., Fujio, Y., Takahashi, K., Azuma, J. J. Biol. Chem. (2007) [Pubmed]
  27. Inhibition of TNF-alpha-induced NF-kappaB activation and IL-8 release in A549 cells with the proteasome inhibitor MG-132. Fiedler, M.A., Wernke-Dollries, K., Stark, J.M. Am. J. Respir. Cell Mol. Biol. (1998) [Pubmed]
  28. p38 MAPK and NF-kappaB mediate COX-2 expression in human airway myocytes. Singer, C.A., Baker, K.J., McCaffrey, A., AuCoin, D.P., Dechert, M.A., Gerthoffer, W.T. Am. J. Physiol. Lung Cell Mol. Physiol. (2003) [Pubmed]
  29. Proteasome inhibition improves fractionated radiation treatment against non-small cell lung cancer: an antioxidant connection. Grimes, K.R., Daosukho, C., Zhao, Y., Meigooni, A., St Clair, W. Int. J. Oncol. (2005) [Pubmed]
  30. Mechanism of action of superactive vitamin D analogs through regulated receptor degradation. Jääskeläinen, T., Ryhänen, S., Mahonen, A., DeLuca, H.F., Mäenpää, P.H. J. Cell. Biochem. (2000) [Pubmed]
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