Regulation of cytochrome P450 4F11 by nuclear transcription factor-κB.
Although the mechanisms that regulate CYP4F genes have been and are currently being studied in a number of laboratories, the specific mechanisms for the regulation of these genes are not yet fully understood. This study shows that nuclear factor κB of the light-chain-enhancer in activated B cells (NF-κB) can inhibit CYP4F11 expression in human liver carcinoma cell line (HepG2) as summarized below. Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, has been shown to activate NF-κB signaling while also activating the c-Jun NH(2)-terminal kinase (JNK) signaling pathway. Other studies have reported that JNK signaling can up-regulate CYP4F11 expression. The results of this study demonstrate that in the presence of TNF-α and the specific NF-κB translocation inhibitor N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (IMD-0354), there is a greater increase in CYP4F11 expression than that elicited by TNF-α alone, indicating that NF-κB plays an inhibitory role. Moreover, NF-κB stimulation by overexpression of mitogen-activated protein kinase kinase kinase inhibited CYP4F11 promoter expression. CYP4F11 promoter inhibition can also be rescued in the presence of TNF-α when p65, a NF-κB protein, is knocked down. Thus, NF-κB signaling pathways negatively regulate the CYP4F11 gene.
Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, 6431 Fannin St., Houston, TX 77225, USA.
Jordan C
JC
Bell
Henry W
HW
Strobel
D001483:Base Sequence; D001665:Binding Sites / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism* / Q000502:physiology; D000072470:Cytochrome P450 Family 4; D056945:Hep G2 Cells; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D016328:NF-kappa B; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C492722:CYP4F11 protein, human