Suppressor of cytokine signaling-1 (SOCS-1), also known as STAT-induced STAT inhibitor-1 (SSI-1), is a negative feedback molecule for cytokine signaling, and its in vivo deletion induces fulminant hepatitis. However, elimination of the STAT1 or STAT6 gene or deletion of NKT cells substantially prevented severe hepatitis in SOCS-1-deficient mice, while administration of IFN-gamma and IL-4 accelerated its development. SOCS-1 deficiency not only sustained IFN-gamma/IL-4 signaling but also eliminated the cross-inhibitory action of IFN-gamma on IL-4 signaling. These results suggest that SOCS-1 deficiency-induced persistent activation of STAT1 and STAT6, which would be inhibited by SOCS-1 under normal conditions, may induce abnormal activation of NKT cells, thus leading to lethal pathological changes in SOCS-1-deficient mice.

Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1) is known to function as a negative feedback regulator of cytokine signaling, but it is unclear whether it is involved in other biological events. Here, we show that SSI-1 participates and plays an important role in the insulin signal transduction pathway. SSI-1–deficient mice showed a significantly low level of blood sugar. While the forced expression of SSI-1 reduced the phosphorylation level of insulin receptor substrate 1 (IRS-1), SSI-1 deficiency resulted in sustained phosphorylation of IRS-1 in response to insulin. Furthermore, SSI-1 achieves this inhibition both by binding directly to IRS-1 and by suppressing Janus kinases. These findings suggest that SSI-1 acts as a negative feedback factor also in the insulin signal transduction pathway through the suppression of IRS-1 phosphorylation.

Four Ca(2+)-dependent, N-acetylgalactosamine/galactose-specific lectins were purified from the marine invertebrate, Cucumaria echinata (Holothuroidea), by column chromatography on lactosyl-Sepharose 4B, Sephacryl S-200, and Q-Sepharose. The molecular masses of these lectins were estimated to be 27 kDa (CEL-I), 35 kDa (CEL-II), 45 kDa (CEL-III), and 68 kDa (CEL-IV) on SDS-PAGE under nonreducing conditions. Among these lectins, CEL-I and CEL-IV strongly agglutinated rabbit and human erythrocytes, and were found to recognize N-acetylgalactosamine and galactose-containing carbohydrates from the results of a hemagglutination inhibition assay. In contrast, CEL-II failed to agglutinate any erythrocytes tested, although its carbohydrate-binding ability was confirmed by a carbohydrate-binding assay involving asialofetuin-horseradish peroxidase. Interestingly, CEL-III caused hemolysis of rabbit and human erythrocytes, while it showed only hemagglutination of chicken and horse erythrocytes at relatively high concentrations. The hemolytic activity of CEL-III was also dependent on the Ca(2+)-concentration, and inhibited by N-acetylgalactosamine and galactose-containing carbohydrates, suggesting that the hemolysis was caused by Ca(2+)-dependent binding of CEL-III to specific carbohydrate chains on the erythrocyte surface and the following partial destruction of the membrane.

The chromosomes of eukaryotic cells possess many potential DNA replication origins, of which a subset is selected in response to the cellular environment, such as the developmental stage, to act as active replication start sites. The mechanism of origin selection is not yet fully understood. In this review, we summarize recent observations regarding replication origins and initiator proteins in various organisms. These studies suggest that the DNA-binding specificities of the initiator proteins that bind to the replication origins and promote DNA replication are primarily responsible for origin selection. We particularly focus on the importance of transcription factors in the origin selection process. We propose that transcription factors are general regulators of the formation of functional complexes on the chromosome, including the replication initiation complex. We discuss the possible mechanisms by which transcription factors influence the selection of particular origins.