The Journal of immunology : official journal of the American Association of Immunologists
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The activation of NF-kappa B consists of at least three steps: degradation of I kappa B alpha, translocation of NF-kappa B into the nucleus, ai post-translational modification of NF-kappa B (e.g., phosphorylation of p65). In the present study, we found that a novel quinone derivative E3330 selectively inhibited NF-kappa B-mediated gene expression without affecting any of these steps. E3330, when included in the culture medium, suppressed NF-kappa B DNA-binding activity in PMA-induced Jurkat cell nuclear extracts, suggesting that the inhibition by E3330 of NF-kappa B-mediated gene expression was due to its ability to suppress NF-kappa B DNA-binding activity. ⋯ Moreover, a major polypeptide with a molecular mass of 40 kDa was found to be in the highly purified fraction containing the NF-kappa B-enhancing activity and predominantly bind E3330. Taken together, these results suggest that the NF-kappa B activity, after dissociation from I kappa B, is enhanced by a nuclear factor that is active irrespective of PMA treatment, and the nuclear factor-mediated enhancement is selectively inhibited by E3330. Thus, we conclude that E3330 may belong to a novel class of anti-NF-kappa B drugs.
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TGF-beta 1 induces the cyclin-dependent kinase inhibitor p27Kip1 mRNA and protein in murine B cells.
TGF-beta1 inhibits the cell cycle progression of many types of cells by arresting them in the G1 phase. This cell cycle arrest has been attributed to the regulatory effects of TGF-beta1 on both the levels and the activities of the G1 cyclins and their kinase partners. The activities of these kinases are negatively regulated by a number of proteins, such as p15INK4b, p21WAF1/Cip1, and p27Kip1, that physically associate with cyclins, cyclin-dependent kinases (Cdk), or cyclin-Cdk complexes. ⋯ In contrast to epithelial cells, however, TGF-beta1 had little or no effect on the Cdk4 and p21WAF1/Cip1 protein levels in these B cells. Finally, although several studies suggested a direct role of p53 in TGF-beta1-mediated cell cycle arrest in epithelial cells, TGF-beta1 inhibited cell cycle progression in CH31 even in the absence of wild-type p53. Taken together, these results suggest that TGF-beta1 induces G1 arrest in B cells primarily through a p53-independent up-regulation of p27Kip1 protein.