geoscience.net logo
+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

NADPH oxidase activity is essential for Keap1/Nrf2-mediated induction of GCLC in response to 2-indol-3-yl-methylenequinuclidin-3-ols


, : NADPH oxidase activity is essential for Keap1/Nrf2-mediated induction of GCLC in response to 2-indol-3-yl-methylenequinuclidin-3-ols. Cancer Research 63(17): 5636-5645

Glutamate cysteine ligase, the rate-limiting enzyme for the synthesis of glutathione, represents an important component of chemoprevention paradigms. GCLC and GCLM, the genes encoding glutamate cysteine ligase subunits, are induced by indoles, such as indomethacin. Novel functionalized indole analogues and other structurally related compounds were synthesized and used for a comparative structure analysis of GCLC induction. Use of mouse embryo fibroblasts null for Nrf2 (nuclear factor-erythroid 2p45-related transcription factor) and HepG2 cells overexpressing Keap1 demonstrated that indole analogue-mediated GCLC expression was regulated by Nrf2-Keap1 interactions. Indole analogues capable of inducing GCLC were found to increase NADPH oxidase activity. Indole analogues unable to induce GCLC did not increase oxidase activity. HepG2 cells transfected with FLAG/Keap1 were exposed to indomethacin, and the redox state of Keap1 cysteine residues was assessed. The data indicated that Keap1 exhibited several oxidation states that were sensitive to indomethacin treatment. These indomethacin-mediated changes in thiol oxidation states were suppressed by diphenyleneiodonium, a NADPH oxidase inhibitor. Diphenyleneiodonium also suppressed indole analogue-mediated increases in GCLC mRNA. In summary, the use of the indole analogues identified NADPH oxidase activity as a novel upstream activity regulating Nrf2/Keap1 signaling of GCLC, provided data supporting the hypothesis that Keap1 is a downstream effector for oxidase activity, and afforded in vivo data to support the hypothesis that Keap1 thiols can act as molecular sensors of reactive oxygen species. Finally, the comparative structure analysis suggests that 2-indol-3-yl-methylenequinuclidin-3-ols may represent a prototype for the development of novel chemopreventative agents able to activate Keap1/Nrf2 signaling.

US$29.90

PMID: 14500406


Other references

Gray, J., 1933: Studies in animal locomotion. I. The movement of fish, with special reference to the eel. Journal of Experimental Biology London, 101: 88-104

Harrison, A.T., 1987: Appointment systems: feasibility study of a new approach. Patients in a semirural dispensing practice were asked to determine how much time they required when booking an appointment. A comparison was made between their estimates and the actual time taken. Patients' estimates proved sufficiently accu...

Sarosi, G.A.; Silver, M.A.; Ben-David, K.; Behrns, K.E., 2015: Training outcomes of preliminary surgical residents in a university and Veterans Affairs surgical residency. Nearly 1400 medical students enter preliminary surgical residency each year; placing some of these students into categorical surgical training is an important component of building the future surgical workforce. To examine the training outcomes of...

Anonymous, 2007: Not Available. Mmw Fortschritte der Medizin 149(18): 26-33

Verma, A.; Kulkarni, S.K.; Nayar, U., 1993: Effect of D1- and D2-dopamine agonists on neocortical and hippocampal EEG activity of rat brain: modulation of rimcazole effect. The effect of selective D-1- and D-2-dopamine (DA) receptor stimulation on neocortical and hippocampal electroencephalographic (EEG) activity of rat brain was studied The modulation of the effect of rimcazole, a sigma receptor antagonist, by D-1-...

Goodyear, N.; Murthy, J.N.; Soldin, S.J., 1997: The 37 kDa immunophilin has uracil DNA glycosylase but not rotamase activity. Clinical Biochemistry 30(6): 497-499

Pyne S.G.; Bloem P.; Chapman S.L.; Griffith R.; Dixon C.E., 1990: Stereochemistry of the intermolecular and intramolecular conjugate additions of amines and anions to chiral e and z vinyl sulfoxides total synthesis of r dextro carnegine and dextro and levo sedamine. The intramolecular addition of incipient amine anions to chiral (E)- and (Z)-vinyl sulfoxides occurs in the same diastereofacial sense, giving chiral isoquinoline and piperidine derivatives that differ in relative stereochemistry at C-2. In contra...

Valkanov, A., 1936: Versuch einer Revision dor Rhizopodengattung Cochliopodium Hertw. and Less. SitsBer. Gesellschaft Naturforschender Freunde, 92-101

Noori, M.H.ssein; Behnam, B., 2000: The effects of pregnant rabbits gentamicin consumption on next generations testes development. Toxicology Letters (Shannon) 116(Suppl 1): 89, September 1st

Ishihama, J.; Tottori, M., 1963: Measures to prevent threatened abortion. Obstetrical and Gynecological Therapy 6: 622-627