Unlike the well defined T helper type 2 cytokine locus, little is known about the regulatory elements that govern the expression of Ifng, which encodes the 'signature' T helper type 1 cytokine interferon-gamma. Here our evolutionary analysis showed that the mouse Ifng locus diverged from the ancestral locus as a result of structural rearrangements producing deletion of the neighboring gene encoding interleukin 26 and disrupting synteny 57 kilobases upstream of Ifng. Proximal to that disruption, we identified by high-resolution mapping many regions with CD4+ T cell subset-specific epigenetic modifications. A subset of those regions represented enhancers, whereas others blocked the activity of upstream enhancers or insulated Ifng from neighboring chromatin. Our findings suggest that proper expression of Ifng is maintained through the collective action of multiple distal regulatory elements present in a region of about 100 kilobases flanking Ifng.
The Src family kinase Lck is crucial for initiation of T cell antigen receptor (TCR) signaling. Lck is tightly controlled to prevent erroneous immune activation, yet allows rapid responses over a range of sensitivities to antigens. Here, using an analog-sensitive Csk we report that Lck is dynamically controlled by a Csk:CD45-controlled equilibrium in T cells. By rapidly inhibiting Csk, we show that changes in this equilibrium are sufficient for activation of the canonical TCR signaling pathways independent of TCR stimulation. The activated signaling pathways show sustained and marked hyperphosphorylation, revealing a feedback circuit that is sensitive to basal signaling activity and is capable of adapting to changes in basal signal transduction machinery. We identify the inhibitory adaptor molecule Dok-1 as a candidate in the adaptive response to alterations in basal signaling activity. Our results also suggest a novel role for Csk in terminating or dampening of TCR signals.
The remarkable variation in prostate cancer clinical behavior represents an opportunity to identify and understand molecular features that can be used to stratify patients into clinical subgroups for more precise outcome prediction and treatment selection. Significant progress has been made in recent years in establishing the composition of genomic and epigenetic alterations in localized and advanced prostate cancers using array-based technologies and next generation sequencing approaches. The results of these efforts shed new light on our understanding of this disease and point to subclasses of prostate cancer that exhibit distinct vulnerabilities to therapeutics. The goal of this review is to categorize the genomic data and, where available, corresponding expression, functional, or related therapeutic information, from recent large-scale and in-depth studies that demonstrate a new appreciation for the molecular complexity of this disease. We focus on how these results inform our growing understanding of the mechanisms that promote genetic instability, as well as routes by which specific genes and biological pathways may serve as biomarkers or potential targets for new therapies. We summarize data that indicate the presence of genetic subgroups of prostate cancers and demonstrate the high level of intra- and intertumoral heterogeneity, as well as updated information on disseminated and circulating tumor cells. The integrated analysis of all types of genetic alterations that culminate in altering critical biological pathways may serve as the impetus for developing new therapeutics, repurposing agents used currently for treating other malignancies, and stratifying early and advanced prostate cancers for appropriate interventions.
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