FOXA1 regulates alternative splicing in prostate cancer.

Dysregulation of alternative splicing in prostate cancer is linked to transcriptional programs activated by AR, ERG, FOXA1, and MYC. Here, we show that FOXA1 functions as the primary orchestrator of alternative splicing dysregulation across 500 primary and metastatic prostate cancer transcriptomes. We demonstrate that FOXA1 binds to the regulatory regions of splicing-related genes, including HNRNPK and SRSF1.

A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia.

The adaptive cellular response to low oxygen tensions is mediated by the hypoxia-inducible factors (HIFs), a family of heterodimeric transcription factors composed of HIF-α and HIF-β subunits. Prolonged HIF expression is a key contributor to cellular transformation, tumorigenesis and metastasis. As such, HIF degradation under hypoxic conditions is an essential homeostatic and tumour-suppressive mechanism.

Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins.

As core components of the microRNA-induced silencing complex (miRISC), Argonaute (AGO) proteins interact with TNRC6 proteins, recruiting other effectors of translational repression/mRNA destabilization. Here, we show that LIMD1 coordinates the assembly of an AGO-TNRC6 containing miRISC complex by binding both proteins simultaneously at distinct interfaces. Phosphorylation of AGO2 at Ser 387 by Akt3 induces LIMD1 binding, which in turn enables AGO2 to interact with TNRC6A and downstream effector DDX6.

The hypoxic tumor microenvironment: driving the tumorigenesis of non-small-cell lung cancer.

Since the application of molecular biology in cancer biology, lung cancer research has classically focused on molecular drivers of disease. One such pathway, the hypoxic response pathway, is activated by reduced local oxygen concentrations at the tumor site. Hypoxia-driven gene and protein changes enhance epithelial-to-mesenchymal transition, remodel the extracellular matrix, drive drug resistance, support cancer stem cells and aid evasion from immune cells.

Mitochondrial superoxide generation enhances P2X7R-mediated loss of cell surface CD62L on naive human CD4+ T lymphocytes.

Migration of naive CD4(+) T lymphocytes into lymphoid tissue is essential for their activation and subsequent roles in adaptive immunity. The adhesion molecule L-selectin (CD62L), critical for this process, is highly expressed on naive CD4(+) T lymphocytes and is downregulated upon T lymphocyte activation. We demonstrate protein expression of P2X7R on naive CD4(+) T lymphocytes and show functional channel activity in whole-cell patch clamp recordings.

Inhibition of PI3K signaling spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies.

The phosphoinositide 3-kinase/mammalian target of rapamycin/protein kinase B (PI3K/mTOR/Akt) signaling pathway is central to a plethora of cellular mechanisms in a wide variety of cells including leukocytes. Perturbation of this signaling cascade is implicated in inflammatory and autoimmune disorders as well as hematological malignancies. Proteins within the PI3K/mTOR/Akt pathway therefore represent attractive targets for therapeutic intervention.

Evidence that the lipid phosphatase SHIP-1 regulates T lymphocyte morphology and motility.

SHIP-1 negatively regulates the PI3K pathway in hematopoietic cells and has an emerging role in T lymphocyte biology. PI3K and SHIP can regulate cell migration in leukocytes, particularly in neutrophils, although their role in T cell migration has been less clear. Therefore, we sought to explore the role of SHIP-1 in human CD4(+) T lymphocyte cell migration responses to chemoattractants using a lentiviral-mediated expression system and a short hairpin RNA approach.

PI3K isoforms as drug targets in inflammatory diseases: lessons from pharmacological and genetic strategies.

Inflammation protects the body against infection and injury, but it is a process that can become dysregulated with deleterious consequences, including the development of rheumatoid arthritis, inflammatory bowel disease, psoriasis and multiple sclerosis. In recent years, inflammation has also been demonstrated to play a key role in other widely prevalent diseases not previously considered to have inflammatory etiologies, such as Alzheimer's disease, cardiovascular diseases and cancer. The current anti-inflammatory therapies such as steroids, NSAIDs and antihistamines are mainly based on inhibiting the synthesis or action of inflammatory mediators.