STAT6 and STAT1 are essential antagonistic regulators of cell survival in classical Hodgkin lymphoma cell line.

Classical Hodgkin lymphoma (cHL) is a malignant lymphoid disorder characterized by aberrant activation of signaling pathways. Constitutive activation of several components of the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has been observed in Hodgkin and Reed/Sternberg cells, the tumor cells of cHL. In this study, we investigate the function of STAT6 in cHL cell lines and show that STAT6 promotes survival of these cells. Microarray expression analysis of STAT6-shRNA (short hairpin RNA)-expressing cHL cell lines was carried out to analyze the STAT6-mediated survival mechanism. Some of the identified genes with potentially important regulatory functions were also interleukin (IL)-4 dependently regulated in Ramos B cells and binding of STAT6 to the regulatory regions of several genes could be confirmed, indicating that these are direct STAT6 target genes. Importantly, STAT6 knockdown increased the expression and activation of STAT1 as well as the expression of known STAT1 target genes, indicating a cross-regulation between these signaling molecules. Forced expression of STAT1 was able to induce apoptosis in cHL cell line L1236. These findings indicate that both STAT6 and STAT1 can act as important antagonistic regulators in the pathogenesis of cHL.

The role of STATs in inflammation and inflammatory diseases.

The immune response is regulated by the concerted action of pro- and anti-inflammatory cytokines. The deregulation of this process causes immunological disorders like allergic and autoimmune diseases. The Janus Kinase (JAK)--Signal transducer and activator of transcription (STAT) pathway is one major signaling pathway converting the cytokine signal into gene expression programs regulating the proliferation and differentiation of the immune cells. Several members of the STAT protein family in particular STAT1, STAT2, STAT3, STAT4 and STAT6 act as transcription factors in modulating pro- and anti-inflammatory responses. Here we review the evidence for the involvement of the different STAT proteins in inflammation, autoimmune and allergic diseases. We discuss novel approaches to interfere with the function of these signaling transcription factors for therapeutic purpose.

The carboxyl-terminal domain of the granulocyte colony-stimulating factor receptor uncouples ribosomal biogenesis from cell cycle progression in differentiating 32D myeloid cells.

Translational regulation plays an important role in development. In terminally differentiating cells a decrease in translation rate is common, although the regulatory mechanisms are unknown. We utilized 32Dcl3 myeloblast cells to investigate translational regulation during granulocyte colony-stimulating factor (G-CSF)-induced differentiation. G-CSF causes a significant decrease in translation rate compared with interleukin-3, which is a mitogen for these cells. Although these two cytokines exhibit modest differences in their effect on translation factor phosphorylation, they exhibit dramatic differences in their effect on ribosomal abundance and ribosomal DNA transcription. However, because both cytokines stimulate cell cycling, G-CSF induces a dissociation of ribosomal biogenesis from cell cycle progression. This uncoupling of ribosomal biogenesis from cell cycle progression appears to be closely related to the transmission of a differentiation signal, because it is not observed in cells expressing a carboxyl-terminally truncated G-CSF receptor, which supports proliferation but not differentiation of these cells. Because a similar event occurs early in differentiation of murine erythroleukemic cells, this suggests that ribosomal content is a common target of differentiating agents.

A novel hydroxyethyl starch (Voluven) for effective perioperative plasma volume substitution in cardiac surgery.

PURPOSE: To compare the new hydroxyethyl starch HES 130/0.4 (Voluven) and the standard HES 200/0.5 (pentastarch) regarding effectiveness for plasma volume substitution and safety of large volumes in heart surgery. METHODS: Fifty-nine patients scheduled for coronary artery bypass grafting were enrolled in a prospective, randomised, double-blind, parallel-group, multicentre, clinical, phase III study. Hydroxyethyl starch was used as the exclusive artificial colloid for acute normovolemic hemodilution, priming of the heart lung machine, and for intra- and postoperative plasma volume substitution from induction of anesthesia until 16 hr after the end of surgery. Efficacy was evaluated by comparing the amount of colloid infused, hemodynamics, and colloid osmotic pressure (COP). Safety endpoints were blood loss, the use of allogeneic blood products, coagulation variables, and adverse events. RESULTS: Effectiveness, as assessed by the total amount of infused HES volumes within the treatment period, was similar between HES 130/0.4 and HES 200/0.5 (2,550 mL +/- 561 mL vs 2,466 mL +/- 516 mL). Also, no differences were found for the use of other colloids (pasteurised plasma), hemodynamics, and COP In HES 130/0.4 patients, the postoperative increase of von-Willebrand factor (vWF) was higher (P < 0.01), blood loss was lower, and less packed red blood cells were transfused. CONCLUSION: Hydroxyethyl starch 130/0.4 is an effective plasma volume expander in heart surgery and may be used as the sole artificial colloid to cover the perioperative period. We found a reduced influence of HES 130/0.4 on the physiologic postoperative increase of vWF.

Inducers of erythroleukemic differentiation cause messenger RNAs that lack poly(A)-binding protein to accumulate in translationally inactive, salt-labile 80 S ribosomal complexes.

Translation has an established role in the regulation of cell growth. Posttranslational modification of translation initiation and elongation factors or regulation of mRNA polyadenylation represent common means of regulating translation in response to mitogenic or developmental signals. Induced differentiation of Friend virus-transformed erythroleukemia cells is accompanied by a rapid decrease in the translation rate of these cells. Although inducers do not alter initiation factor modifications, characterization of their effect on mRNA translation provides evidence that this is mediated by the poly(A)-binding protein (PABP). Inducer exposure results in an increase in the amount of mRNA that sediments at 80 S and a decrease in the amount in polysomes. Although these 80 S ribosomes have characteristics previously attributed to "vacant ribosomal couples," including lability in 500 mM KCl and an inability to incorporate amino acids into protein, we provide evidence that these 80 S complexes are not vacant but contain mRNA that is stably bound to the 40 S subunit, whereas the 60 S subunit is dissociated from the complex by high salt. The absence of eukaryotic initiation factor 2 from these complexes suggests that translation has proceeded through subunit joining. Immunoblotting demonstrates that the mRNAs in these 80 S ribosomal complexes do not contain bound PABP and that this protein is found to be almost exclusively associated with translating polysomes. These data suggest that the PABP plays a role in the accumulation of these 80 S ribosomal.mRNA complexes and may facilitate the formation of translationally active salt-stable ribosomes.