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  • Title: Inhibition of nuclear factor-kappaB DNA binding by organoselenocyanates through covalent modification of the p50 subunit.
    Author: Chen KM, Spratt TE, Stanley BA, De Cotiis DA, Bewley MC, Flanagan JM, Desai D, Das A, Fiala ES, Amin S, El-Bayoumy K.
    Journal: Cancer Res; 2007 Nov 01; 67(21):10475-83. PubMed ID: 17974991.
    Abstract:
    Most known chemopreventive agents including certain selenium compounds suppress the activation of the nuclear factor kappaB (NF-kappaB), but the mechanisms remain largely elusive. Toward this end, we initially showed that the inhibition of NF-kappaB DNA binding by benzyl selenocyanate (BSC) and 1,4-phenylenebis(methylene)selenocyanate (p-XSC) was reversed by the addition of DTT; this suggests the formation of DTT-reducible selenium-sulfur bonds between selenocyanate moieties and cysteine residues in NF-kappaB (p50) protein. Furthermore, the inhibitory effect of selenocyanates on NF-kappaB was not altered in the presence of physiologic level of reduced glutathione (1 mmol/L), suggesting that selenocyanates can also inhibit NF-kappaB in vivo. Using both matrix-assisted laser desorption/ionization-time of flight and tandem mass spectrometry fragmentation, we showed for the first time that the Cys(62) residue in the active site of NF-kappaB (p50) protein was modified by BSC through the formation of a selenium-sulfur bond. In addition, p-XSC-bound NF-kappaB (p50) protein was also detected by a radiotracer method. To provide further support, molecular models of both BSC and p-XSC positioned in the DNA binding pocket of the p50 were constructed through the covalent modification of Cys(62); the models reveal that DNA substrate could be hindered to enter its DNA binding region. This study shows for the first time that BSC and p-XSC may exert their chemopreventive activity, at least in part, by inhibiting NF-kappaB through covalent modification of Cys(62) of the p50 subunit of NF-kappaB.
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