An upstream protein interacts with a distinct protein that binds to the cap site of the human interleukin 1 beta gene.

Interleukin 1 beta (IL-1 beta) is a proinflammatory cytokine that exhibits a wide variety of biological activities. Genomic sequences that mediate the induction of human IL-1 beta gene transcription by lipopolysaccharide and phorbol esters are located more than 2,700 bp upstream of the transcriptional start site (cap site). These upstream elements require additional cap site-proximal (CSP) sequences which are necessary for basal transcription of the human IL-1 beta gene. In addition, these CSP sequences have been shown to mediate both cell type-specific expression of this gene, and trans-activation by some viral proteins. In this study, we report the identification of a novel nuclear protein, termed NF beta C, that binds to a DNA sequence which spans the cap site of the human IL-1 beta gene (positions -12 to +8). We have also identified a second region (positions -305 to -280) containing a putative NF-kappa B binding site. We show here that this region can bind three distinct nuclear proteins. One protein is similar or identical to NF-kappa B, a second protein (termed NF beta B) binds a distinct sequence that substantially overlaps the 5' half of the NF kappa B binding sequence, and a third protein (termed NF beta D) binds a distinct sequence that substantially overlaps the 3' half of the NF kappa B binding sequence. Unlike NF kappa B, NF1 beta B and NF beta D are present in nuclear extracts prepared from unstimulated monocytic cells. Although the NF beta D and NF beta C binding sequences share no significant similarity, each sequence can specifically compete for the binding of either protein to DNA, whereas oligonucleotides containing only the NF kappa B or NF beta B motifs do not compete for the binding of NF beta C or NF beta D. This suggests that NF beta C and NF beta D can specifically interact in vitro, possibly through a common subunit.

Immunoconjugates containing novel maytansinoids: promising anticancer drugs.

The potential of immunoconjugates of cytotoxic drugs for the treatment of cancer has not yet been realized owing to the difficulty of delivering therapeutic concentrations of these drugs to the target cells. In an effort to overcome this problem we have synthesized maytansinoids that have 100- to 1000-fold higher cytotoxic potency than clinically used anticancer drugs. These maytansinoids are linked to antibodies via disulfide bonds, which ensures the release of fully active drug inside the cells. The conjugates show high antigen-specific cytotoxicity for cultured human cancer cells (50% inhibiting concentration, 10 to 40 pM), low systemic toxicity in mice, and good pharmacokinetic behavior.