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The article discusses a randomized phase-two study which determines whether changes in nuclear factor kappa B (NF-ƘB) activity corresponded with changes in the expression of NF-ƘB target genes. In the said study, the newly diagnosed patients with acute myelogenous leukemia (AML) eligible for standard induction chemotherapy were assigned to choline magnesium trisalicylate (CMT) or no CMT.

C-terminal truncations of the NFKB2 p100 gene product have been observed in a number of cases of human cutaneous T cell lymphomas, as well as human B-cell lymphomas and myelomas. The contribution of these alterations to lymphomagenesis is not understood; however, truncation at amino acid 666 to generate 80–85 kD proteins in the HUT78 cell line is associated with addition of a short (serine-alanine-serine) fusion at the 3′ end of p80HT, as well as with increased expression of NFKB2 mRNA. We therefore examined the effects of p80HT on the regulation of NFKB2 expression, as well as the properties of a series of other tumor-associated, and site directed mutations of NFKB2. While p80HT had not itself acquired novel transcriptional activation properties with respect to the NFKB2 P1 or P2 promoters or the IL-6 κB promoter, p80HT had lost the potent inhibitory (IκB-like) activity associated with the wild-type, p100 gene product. Loss of the inhibitory property depended on the SAS residues in the fusion protein, direct truncation at aa666 was fully inhibitory, as was a substitution of three alanines for the SAS residues. The presence of as few as two C-terminal ankyrin motifs was sufficient for inhibition of NF-κB-mediated transcriptional activation. Assays of a series of additional lymphoma-associated NF-κB-2 truncation suggested that the C-terminal truncation associated with these proteins was also associated with a loss of the IκB-like activities of p100 NF-κB-2, for at least some NF-κB target promoters. Thus, the loss of IκB-like activity of lymphoma-associated NFKB2 mutations may play an important role in the genesis of a subset of human lymphomas. Oncogene (2000) 19, 1334–1345. [ABSTRACT FROM AUTHOR]

It is a long-standing observation that inflammatory responses and infections decrease drug metabolism capacity in human and experimental animals. Cytochrome P-450 3A4 cyp304 is responsible for the metabolism of over 50% of current prescription drugs, and cyp3a4 expression is transcriptionally regulated by pregnane X receptor (PXR), which is a ligand-dependent transcription factor. In this study, we report that NF-κB activation by lipopolysaccharide and tumor necrosis factor-a plays a pivotal role in the suppression of cyp3a4 through interactions of NF-κB with the PXR-retinoid X receptor (RXR) complex. Inhibition of NF-κB by NF-κB-specific suppressor SRIκBα reversed the suppressive effects of lipopolysaccharide and tumor necrosis factor-α. Furthermore, we showed that NF-κB p65 disrupted the association of the PXR-RXRα complex with DNA sequences as determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assays. NF-κB p65 directly interacted with the DNA-binding domain of RXRα and may prevent its binding to the consensus DNA sequences, thus inhibiting the transactivation by the PXR-RXRα complex. This mechanism of suppression by NF-κB activation may be extended to other nuclear receptor-regulated systems where RXRα is a dimerization partner. [ABSTRACT FROM AUTHOR]

Abstract: Human T cell leukemia virus 1 (HTLV-1) gene expression is regulated by both the viral Tax protein and by cellular transcriptional factors. We have previously shown that immune activation stimuli such as phorbol esters (PMA) and phytohemagglutinin (PHA) cooperate with HTLV-1 Tax expression to enhance HTLV-1 gene expression in infected T cells through increased activity of the HTLV-1 LTR. We now extend these studies to demonstrate roles for the T cell receptor complex, Lck, and Ras molecules in the coactivation of the HTLV-1 LTR by Tax and T cell activation stimuli. We also observe coactivation of Tax-responsive cellular promoter elements containing NF-κB and serum response factor (SRF) binding sites by Tax and T cell activation stimuli. These results suggest a model whereby T cell receptor stimulation and Tax expression coactivate HTLV-1 gene expression and cellular gene expression, enhancing activation of latent HTLV-1 and expression of cellular genes involved in disease pathogenesis. [Copyright &y& Elsevier]