Negative regulation of cytokine signaling is important for limiting the intensity and duration of cytokine action and for maintaining homeostasis. Several constitutive mechanisms for suppressing cytokine Jak-STAT signaling have been described. Inducible or regulated inhibition of cytokine signaling is equally important, and much attention has been focused on inhibition mediated through the indu...

Abstract Although the cyclin-dependent kinases CDK4 and CDK6 play fundamental roles in cancer, specific pathways downstream targets by which they exert their tumorigenic effects remain elusive. In this study, we uncover distinct novel functions for these regulating tumor formation metastatic colonization various solid tumors, including those of breast, prostate, pancreas. Combining vivo CRISPR-...

Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of γ oscillations, and cognition. Dysfunction PV disrupts information processing cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation but is also implicated in their adult multidimensional functions. Using a novel v...

Abstract Macrophages are key innate immune cells that important for host defense but their aberrant activation by IFN-γ has been implicated in the pathogenesis of chronic inflammatory diseases such as rheumatoid arthritis (RA). IFN-γ, signals through protein tyrosine kinases JAK1/2 to activate transcription factor STAT1 and drive expression interferon-stimulated genes (ISGs). primed macrophage ...

signal transducers and activators of transcription (stats) are cytoplasmic transcription factors that have a key role in cell fate. stats, a protein family comprised of seven members, are proteins which are latent cytoplasmic transcription factors that convey signals from the cell surface to the nucleus through activation by cytokines and growth factors. the signaling pathways have diverse biol...

Excitatory amino acid transporters (EAATs) terminate signaling in the CNS by clearing released glutamate. Glutamate also evokes an EAAT-mediated Cl(-) current, but its role in CNS signaling is poorly understood. We show in mouse retina that EAAT-mediated Cl(-) currents that were evoked by light inhibit rod pathway signaling. EAATs reside on rod bipolar cell axon terminals where GABA and glycine...

Basal cell carcinoma (BCC) is driven by constitutive activation of the Hedgehog (Hh) signaling pathway, most commonly through loss-of-function mutations in PTCH1. Using animal models, we demonstrate here that microscopic BCC-like tumors initiated loss Ptch1 or gain Smo fail to progress and eventually enter into a dormant state. Because NOTCH1/2 TRP53 are detected human BCC, sought determine if ...

Abstract β-catenin-signaling promotes proliferation and survival in epithelial, neuronal, mesenchymal lineages, but is dispensable for B- T-cell development. β-catenin activation a common oncogenic driver throughout all types of cancer with the exception T-lymphoid malignancies. Unlike epithelial tissues, we found that T-cells consistently lack expression. Instead, both were highly sensitive to...

Owing to their location at the interface with external environment, stem cells of epidermis are particularly exposed environmental variations such as fluctuating temperature. However, little is known about how temperature affects epidermal cell metabolism and behavior. Here we demonstrate that cultured human (HESCs) respond a small drop in through thermos-sensitive TRP channels connected mTOR s...