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Chemical Compound Review

AC1MHKLF     (2Z,3Z)-2,3-bis[amino-(2...

Synonyms: CHEMBL34704, BSPBio_001224, CHEBI:64208, BMK1-B2, CHEBI:257660, ...
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Disease relevance of U 0126

  • To determine whether ERK1/2 was activated by cellular acidosis or TRO was acting via MEK1/2 to activate ERK1/2, cells were pretreated with specific inhibitors of MEK1/2 activity, PD-098059 and U-0126, followed by the addition of TRO or vehicle [1].
  • Ischemia resulted in a 1.8-fold increase in NO generation that was suppressed by inhibitors of ERK1/2 activation (PD-98059 or U-0126) [2].
  • After exposure to H/I, PAD in response to hypercapnia was impaired, but pretreatment with either genistein, tyrphostin A23, U-0126, or PD-98059 partially protected such impairment (17 +/- 1% vs. 4 +/- 1% vs. 9 +/- 1% for sham control, H/I, and H/I + genistein pretreatment, respectively) [3].
  • Similarly, MEK-ERK inhibition significantly increased myocardial infarct size in FGF-2 Tg (12 +/- 3% vehicle vs. 31 +/- 2% U-0126; P < 0.05) but not wild-type (30 +/- 4% vehicle vs. 36 +/- 7% U-0126) hearts [4].
  • Treatment of FGF-2 Tg and wild-type hearts with U-0126, a MEK-ERK pathway inhibitor, significantly reduced recovery of contractile function after global low-flow ischemia-reperfusion injury in FGF-2 Tg (86 +/- 2% vehicle vs. 66 +/- 4% U-0126; P < 0.05) but not wild-type (61 +/- 7% vehicle vs. 67 +/- 7% U-0126) hearts [4].

High impact information on U 0126

  • Proteasome depletion of the tumor lysates, addition of the specific MEK1/2 inhibitor U-0126, or a T187A mutation in recombinant p27 all prevented p27 degradation [5].
  • Moreover, the group IVA phospholipase A2 inhibitor pyrrophenone and the MEK inhibitor U-0126 inhibited AA release and 5-LO translocation in activated PMN, and these effects were also prevented by exogenous AA, demonstrating a functional link between AA release and 5-LO translocation [6].
  • Inhibition of ERK phosphorylation with the specific inhibitors, PD-98059 and U-0126, decreased the [Ca2+]e induction of both COX-2 mRNA and luciferase activity by 70-80% [7].
  • Surprisingly, the MEK1 inhibitors PD 98059 and U 0126 blocked both ERK1/2 and JNK phosphorylation, indicating a novel form of balancing MAPK cascade cross-talk [8].
  • Indeed, concomitant incubation of S 34961 with 10 microM U-0126 (a mitogen-activated protein kinase kinase inhibitor) was found to lead to apoptosis (at 24 h), whereas U-0126 alone had no effect [9].

Chemical compound and disease context of U 0126


Biological context of U 0126


Anatomical context of U 0126

  • These changes were associated with increased apoptosis as measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and immunofluorescent labeling of anti-active caspase-3 in the mesenchyme of explants after U-0126 treatment compared with the control [15].
  • Mitosis characterized by immunolocalization of proliferating cell nuclear antigen was found predominantly in the epithelium and was reduced in U-0126-treated explants [15].
  • Inhibition of MEK with U-0126 did not prevent GLUT4 from translocating to the plasma membrane, nor did it inhibit the subsequent docking and fusion of GLUT4-myc with the plasma membrane [17].
  • Here we report that isoproterenol phosphorylated the protein S6 kinase (p70S6k) in alveolar epithelial cells, which was inhibited by both rapamycin and the MEK1/2 inhibitor U-0126 [18].
  • In ovine middle cerebral arteries (MCA), we measured isometric tension and intracellular free calcium concentration ([Ca(2+)](i)) responses to PKC stimulation [phorbol 12,13-dibutyrate (PDBu), 3 x 10(-6) M] in the absence or presence of ERK1/2 inhibition (U-0126, 10(-5) M) [19].

Associations of U 0126 with other chemical compounds

  • GM-CSF release was inhibited by U 0126 but enhanced by SB 203580 [20].
  • Inhibition of PI3K with LY-294002 blocked Akt phosphorylation and proliferation, whereas U-0126 blocked ERK1/2 phosphorylation but had no effect on proliferation [21].
  • In both age groups, inhibition by U-0126, but not PD-98059, decreased the PHE-induced [Ca2+]i increase; in fact for adult, this eliminated any significant [Ca2+]i increase [22].
  • To evaluate the functional role of MAPKs in LC-induced cytokine responses, we tested the effects of U-0126, an ERK inhibitor; SP-600125, an inhibitor of JNK; SB-203580, a p38 inhibitor; and curcumin, a JNK-AP-1 inhibitor, all added to media before 4-h exposure to 1.5 mg/ml kappa(1)-LC [23].
  • Coadministration of either of the PTK inhibitors genistein or tyrphostin A23 or the MAPK inhibitors U-0126 or PD-98059 with NOC/oFQ (10(-10) M) partially prevented the inhibition of hypercapnic PAD compared with that observed in their absence (21 +/- 2% vs. 17 +/- 1% for genistein) [3].

Gene context of U 0126

  • Eotaxin release was inhibited by SB 203580 and U 0126, whereas RANTES release was prevented by U 0126 only [20].
  • Inhibition of MAPK activity by MEK inhibitor U-0126 abolished EGF-induced DNA synthesis [24].
  • U-0126 also inhibited an increase in nuclear factor-kappaB and activator protein-1 DNA-binding activity of MCP-1 promoter by protein overload in mProx cells [25].
  • Inhibition of ERK activation with the MEK inhibitors PD-98059 and U-0126 as well as the Src family kinase inhibitor PP2 completely blocked the effect of DABK to increase p27Kip1 and partially reversed the DABK-mediated inhibition of PDGF-stimulated proliferation [26].
  • U-0126 also inhibited IL-13, and TNF-alpha induced mRNA expression [27].

Analytical, diagnostic and therapeutic context of U 0126


  1. Troglitazone's rapid and sustained activation of ERK1/2 induces cellular acidosis in LLC-PK1-F+ cells: physiological responses. Oliver, R., Friday, E., Turturro, F., Lacy, A., Welbourne, T. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  2. Signaling pathway for nitric oxide generation with simulated ischemia in flow-adapted endothelial cells. Wei, Z., Al-Mehdi, A.B., Fisher, A.B. Am. J. Physiol. Heart Circ. Physiol. (2001) [Pubmed]
  3. PTK, MAPK, and NOC/oFQ impair hypercapnic cerebrovasodilation after hypoxia/ischemia. Jagolino, A.L., Armstead, W.M. Am. J. Physiol. Heart Circ. Physiol. (2003) [Pubmed]
  4. Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade. House, S.L., Branch, K., Newman, G., Doetschman, T., Schultz, J.e.l. .J. Am. J. Physiol. Heart Circ. Physiol. (2005) [Pubmed]
  5. Blockade of the epidermal growth factor receptor tyrosine kinase suppresses tumorigenesis in MMTV/Neu + MMTV/TGF-alpha bigenic mice. Lenferink, A.E., Simpson, J.F., Shawver, L.K., Coffey, R.J., Forbes, J.T., Arteaga, C.L. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  6. Arachidonic acid regulates the translocation of 5-lipoxygenase to the nuclear membranes in human neutrophils. Flamand, N., Lefebvre, J., Surette, M.E., Picard, S., Borgeat, P. J. Biol. Chem. (2006) [Pubmed]
  7. Extracellular calcium is a potent inducer of cyclo-oxygenase-2 in murine osteoblasts through an ERK signaling pathway. Choudhary, S., Wadhwa, S., Raisz, L.G., Alander, C., Pilbeam, C.C. J. Bone Miner. Res. (2003) [Pubmed]
  8. MEKK1 controls neurite regrowth after experimental injury by balancing ERK1/2 and JNK2 signaling. Waetzig, V., Herdegen, T. Mol. Cell. Neurosci. (2005) [Pubmed]
  9. Decrease in survival threshold of quiescent colon carcinoma cells in the presence of a small molecule integrin antagonist. Burbridge, M.F., Venot, V., Casara, P.J., Perron-Sierra, F., Hickman, J.A., Tucker, G.C. Mol. Pharmacol. (2003) [Pubmed]
  10. A role for PYK2 in ANG II-dependent regulation of the PHAS-1-eIF4E complex by multiple signaling cascades in vascular smooth muscle. Rocic, P., Jo, H., Lucchesi, P.A. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  11. Role of ERK1/2 in uterine contractility and preterm labor in rats. Li, Y., Je, H.D., Malek, S., Morgan, K.G. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2004) [Pubmed]
  12. Interleukin-6 and interleukin-15 are selectively regulated by lipopolysaccharide and interferon-gamma in primary pig adipocytes. Ajuwon, K.M., Jacobi, S.K., Kuske, J.L., Spurlock, M.E. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2004) [Pubmed]
  13. Bleomycin upregulates expression of gamma-glutamylcysteine synthetase in pulmonary artery endothelial cells. Day, R.M., Suzuki, Y.J., Lum, J.M., White, A.C., Fanburg, B.L. Am. J. Physiol. Lung Cell Mol. Physiol. (2002) [Pubmed]
  14. Roles of insulin-like growth factor II in cardiomyoblast apoptosis and in hypertensive rat heart with abdominal aorta ligation. Lee, S.D., Chu, C.H., Huang, E.J., Lu, M.C., Liu, J.Y., Liu, C.J., Hsu, H.H., Lin, J.A., Kuo, W.W., Huang, C.Y. Am. J. Physiol. Endocrinol. Metab. (2006) [Pubmed]
  15. MEK-1/2 inhibition reduces branching morphogenesis and causes mesenchymal cell apoptosis in fetal rat lungs. Kling, D.E., Lorenzo, H.K., Trbovich, A.M., Kinane, T.B., Donahoe, P.K., Schnitzer, J.J. Am. J. Physiol. Lung Cell Mol. Physiol. (2002) [Pubmed]
  16. Differential expression of cell-cell adhesion proteins and cyclin D in MEK1-transdifferentiated MDCK cells. Marschitz, I., Lechner, J., Mosser, I., Dander, M., Montesano, R., Schramek, H. Am. J. Physiol., Cell Physiol. (2000) [Pubmed]
  17. MEK inhibitors impair insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Harmon, A.W., Paul, D.S., Patel, Y.M. Am. J. Physiol. Endocrinol. Metab. (2004) [Pubmed]
  18. Beta-adrenergic agonists regulate Na-K-ATPase via p70S6k. Pesce, L., Comellas, A., Sznajder, J.I. Am. J. Physiol. Lung Cell Mol. Physiol. (2003) [Pubmed]
  19. PKC-induced ERK1/2 interactions and downstream effectors in ovine cerebral arteries. Zhao, Y., Zhang, L., Longo, L.D. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2005) [Pubmed]
  20. Inhibitors of mitogen-activated protein kinases differentially regulate eosinophil-activating cytokine release from human airway smooth muscle. Hallsworth, M.P., Moir, L.M., Lai, D., Hirst, S.J. Am. J. Respir. Crit. Care Med. (2001) [Pubmed]
  21. Requirement of the epidermal growth factor receptor in renal epithelial cell proliferation and migration. Zhuang, S., Dang, Y., Schnellmann, R.G. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  22. Extracellular signal-regulated kinases and contractile responses in ovine adult and fetal cerebral arteries. Zhao, Y., Long, W., Zhang, L., Longo, L.D. J. Physiol. (Lond.) (2003) [Pubmed]
  23. Role of MAPK pathways in light chain-induced cytokine production in human proximal tubule cells. Sengul, S., Zwizinski, C., Batuman, V. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  24. EGF stimulates mesangial cell mitogenesis via PI3-kinase-mediated MAPK-dependent and AKT kinase-independent manner: involvement of c-fos and p27Kip1. Mahimainathan, L., Ghosh-Choudhury, N., Venkatesan, B.A., Danda, R.S., Choudhury, G.G. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  25. Involvement of ERK pathway in albumin-induced MCP-1 expression in mouse proximal tubular cells. Takaya, K., Koya, D., Isono, M., Sugimoto, T., Sugaya, T., Kashiwagi, A., Haneda, M. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  26. Bradykinin B1 receptor blocks PDGF-induced mitogenesis by prolonging ERK activation and increasing p27Kip1. Dixon, B.S., Evanoff, D., Fang, W.B., Dennis, M.J. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  27. IL-13 and IL-4 cause eotaxin release in human airway smooth muscle cells: a role for ERK. Moore, P.E., Church, T.L., Chism, D.D., Panettieri, R.A., Shore, S.A. Am. J. Physiol. Lung Cell Mol. Physiol. (2002) [Pubmed]
  28. Endogenous adenosine protects preconditioned heart during early minutes of reperfusion by activating Akt. Solenkova, N.V., Solodushko, V., Cohen, M.V., Downey, J.M. Am. J. Physiol. Heart Circ. Physiol. (2006) [Pubmed]
  29. Effects of mitogen-activated protein kinase inhibitors on cerebral vasospasm in a double-hemorrhage model in dogs. Tibbs, R., Zubkov, A., Aoki, K., Meguro, T., Badr, A., Parent, A., Zhang, J. J. Neurosurg. (2000) [Pubmed]
  30. Hyperphosphorylation at serine 199/202 of tau factor in the gerbil hippocampus after transient forebrain ischemia. Morioka, M., Kawano, T., Yano, S., Kai, Y., Tsuiki, H., Yoshinaga, Y., Matsumoto, J., Maeda, T., Hamada, J., Yamamoto, H., Fukunaga, K., Kuratsu, J. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
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