Cytokine responses can be regulated by a family of proteins termed suppressors of cytokine signaling (SOCS) which can inhibit the JAK/STAT pathway in a classical negative-feedback manner. While the SOCS are thought to target signaling intermediates for degradation, relatively little is known about how their turnover is regulated. Unlike other SOCS family members, we find that SOCS2 can enhance interleukin-2 (IL-2)-and IL-3-induced STAT phosphorylation following and potentiate proliferation in response to cytokine stimulation. As a clear mechanism for these effects, we demonstrate that expression of SOCS2 results in marked proteasome-dependent reduction of SOCS3 and SOCS1 protein expression. Furthermore, we provide evidence that this degradation is dependent on the presence of an intact SOCS box and that the loss of SOCS3 is enhanced by coexpression of elongin B/C. This suggests that SOCS2 can bind to SOCS3 and elongin B/C to form an E3 ligase complex resulting in the degradation of SOCS3. Therefore, SOCS2 can enhance cytokine responses by accelerating proteasome-dependent turnover of SOCS3, suggesting a mechanism for the gigantism observed in SOCS2 transgenic mice.Cytokines such as interleukin-2 (IL-2) regulate the immune response via interaction with cell surface receptors on target cells. These receptors interact with cytoplasmic tyrosine kinases, specifically, members of the Janus kinase (JAK) family, which subsequently phosphorylate signal transducer and activator of transcription (STAT) proteins. Phosphorylation of STATs results in their dimerization and translocation to the nucleus and subsequent transcriptional activation of genes important for proliferation and differentiation (11). Inhibition of these signaling pathways is crucial for the control of the inflammatory response (16). The suppressors of cytokine signaling (SOCS/SSI/CIS) are thought to play a key role in this process and are upregulated by and inhibit the JAK/STAT pathway in a classic negative-feedback manner (7,32,39). Eight SOCS family proteins have been described, CIS (cytokine-inducible SH2 domain-containing protein) and SOCS1 to SOCS7 (10,22,29). These proteins are characterized by two common structural motifs, an SH2 domain and a C-terminal SOCS box. The SOCS box is thought to interact with elongin B/C, part of an E3 ubiquitin ligase complex that targets associated proteins for degradation through the ubiquitin pathway (27). As well as SOCS, a number of other protein subfamilies including the von Hippel-Lindau (VHL) tumor suppressor protein contain this SOCS box motif, indicating that it may have an important and conserved role (17). The SOCS box of VHL associates with an E3 ligase complex and induces the proteasomal degradation of hypoxia-inducible factor 1␣ (40).More recently, Asb, an adipocyte-specific ankyrin and SOCS box-containing protein, has been shown to interact with the adaptor protein APS (adapter protein with PH and SH2 domain) to enable recruitment of elongin B/C to the insulin receptor (43).SOCS1 and SOCS3 are induced ra...

Stromal-derived growth factors are required for normal epithelial growth but are also implicated in tumour progression. We have observed inactivation of the retinoblastoma protein (Rb), through phosphorylation, in cancer-associated fibroblasts in oro-pharyngeal cancer specimens. Rb is well known for its cell-autonomous effects on cancer initiation and progression; however, cell non-autonomous functions of Rb are not well described. We have identified a cell non-autonomous role of Rb, using three-dimensional cultures, where depletion of Rb in stromal fibroblasts enhances invasive potential of transformed epithelia. In part, this is mediated by upregulation of keratinocyte growth factor (KGF), which is produced by the depleted fibroblasts. KGF drives invasion of epithelial cells through induction of MMP1 expression in an AKT-and Ets2-dependent manner. Our data identify that stromal fibroblasts can alter the invasive behaviour of the epithelium, and we show that altered expression of KGF can mediate these functions.

Current or former asthma was reported by 21.3% of the adult population. A history of using biomass fuels when cooking indoors significantly increased the risk of reporting current asthma in this population.

Objective Characterize responses to a NNRTI-based antiretroviral treatment (ART) initiated during acute HIV infection (AHI). Design This was a prospective, single-arm evaluation of once daily, co-formulated emtricitabine/tenofovir/efavirenz initiated during AHI. Methods The primary endpoint is the proportion of responders with HIV RNA <200 copies/mL by week 24. We examined time-to-viral-suppression and CD8 cell activation in relation to baseline participant characteristics. We compared time-to-viral-suppression and viral dynamics using linear mixed effects models between acutely infected participants and chronically-infected controls. Results Between January 2005 and May 2009, 61 AHI participants were enrolled. Of participants whose enrollment date allowed 24 and 48 weeks of follow-up, 47 of 51 (92%) achieved viral suppression to <200 copies/mL by week 24, and 35 of 41 (85.4%) to <50 copies/mL by week 48. The median time from ART initiation to suppression <50 copies/mL was 93 days (range 14–337). Higher HIV RNA levels at ART initiation (p=0.02), but not time from estimated-date-of-infection to ART initiation (p=0.86), were associated with longer time-to-viral-suppression. The median baseline frequency of activated CD8+CD38+HLA-DR+ T-cells was 67% (range 40–95), and was not significantly associated with longer time to viral load suppression (p=0.15). Viremia declined to <50 copies/mL more rapidly in AHI than chronically-infected participants. Mixed model analysis demonstrated similar phase I HIV RNA decay rates between acute and chronically-infected participants, and more rapid viral decline in acutely-infected participants in phase II. Conclusion Once daily emtricitabine/tenofovir/efavirenz initiated during AHI achieves rapid and sustained HIV suppression during this highly infectious period.