| Autor: |
Chen KM; Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA 17033, USA., Spratt TE, Stanley BA, De Cotiis DA, Bewley MC, Flanagan JM, Desai D, Das A, Fiala ES, Amin S, El-Bayoumy K |
| Jazyk: |
angličtina |
| Zdroj: |
Cancer research [Cancer Res] 2007 Nov 01; Vol. 67 (21), pp. 10475-83. |
| DOI: |
10.1158/0008-5472.CAN-07-2510 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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