Jian‐Guo Zhang

The suppressors of cytokine signaling (SOCS) family of proteins act as intracellular inhibitors of several cytokine signal transduction pathways. Their expression is induced by cytokine activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and they act as a negative feedback loop by subsequently inhibiting the JAK/STAT pathway either by direct interaction with activated JAKs or with the receptors. These interactions are mediated at least in part by the SH2 domain of SOCS proteins but these proteins also contain a highly conserved C-terminal homology domain termed the SOCS box. Here we show that the SOCS box mediates interactions with elongins B and C, which in turn may couple SOCS proteins and their substrates to the proteasomal protein degradation pathway. Analogous to the family of F-box-containing proteins, it appears that the SOCS proteins may act as adaptor molecules that target activated cell signaling proteins to the protein degradation pathway.

Although anemia is common in older adults, its prognostic significance is uncertain. A total of 17 030 community-dwelling subjects 66 years and older were identified between July 1 and December 31, 2001, and followed until December 31, 2004. Cox proportional hazards analyses were performed to determine the associations between anemia (defined as hemoglobin < 110 g/L) and hemoglobin and all-cause mortality, all-cause hospitalization, and cardiovascular-specific hospitalization. Overall, there were 1983 deaths and 7278 first hospitalizations. In patients with normal kidney function, adjusting for age, sex, diabetes mellitus, and comorbidity, anemia was associated with an increased risk for death (hazard ratio [HR], 4.29; 95% confidence interval [CI], 3.55-5.12), first all-cause hospitalization (HR, 2.16; 95% CI, 1.88-2.48), and first cardiovascular-specific hospitalization (HR, 2.49; 95% CI, 1.99-3.12). An inverse J-shaped relationship between hemoglobin and all-cause mortality was observed; the lowest risk for mortality occurred at hemoglobin values between 130 to 150 g/L for women and 140 to 170 g/L for men. Anemia is associated with an increased risk for hospitalization and death in community-dwelling older adults. Consideration should be given to redefine "normal" hemoglobin values in the elderly. Clinical trials are also necessary to determine whether anemia correction improves quality or quantity of life in this population.

Suppressor of cytokine signaling-3 (SOCS-3) is one member of a family of intracellular inhibitors of signaling pathways initiated by cytokines that use, among others, the common receptor subunit gp130. The SH2 domain of SOCS-3 has been shown to be essential for this inhibitory activity, and we have used a quantitative binding analysis of SOCS-3 to synthetic phosphopeptides to map the potential sites of interaction of SOCS-3 with different components of the gp130 signaling pathway. The only high-affinity ligand found corresponded to the region of gp130 centered around phosphotyrosine-757 (pY757), previously shown to be a docking site for the tyrosine phosphatase SHP-2. By contrast, phosphopeptides corresponding to other regions within gp130, Janus kinase, or signal transducer and activator of transcription proteins bound to SOCS-3 with weak or undetectable affinity. The significance of pY757 in gp130 as a biologically relevant SOCS-3 docking site was investigated by using transfected 293T fibroblasts. Although SOCS-3 inhibited signaling in cells transfected with a chimeric receptor containing the wild-type gp130 intracellular domain, inhibition was considerably impaired for a receptor carrying a Y-->F point mutation at residue 757. Taken together, these data suggest that the mechanism by which SOCS-3 inhibits the gp130 signaling pathway depends on recruitment to the phosphorylated gp130 receptor, and that some of the negative regulatory roles previously attributed to the phosphatase SHP-2 might in fact be caused by the action of SOCS-3.